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Clinical Trial Results:
Dose-escalating and cohort expansion safety trial of tissue factor specific antibody drug conjugate tisotumab vedotin (HuMax®-TF-ADC) in patients with locally advanced and/or metastatic solid tumors known to express tissue factor

Summary
EudraCT number	2015-001120-29
Trial protocol	GB DK BE HU
Global end of trial date	13 Dec 2017

Results information
Results version number	v1(current)
This version publication date	26 Dec 2018
First version publication date	26 Dec 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GEN702

ISRCTN number

US NCT number

NCT02552121

WHO universal trial number (UTN)

Sponsor organisation name

Genmab A/S

Sponsor organisation address

Kalvebod Brygge 43, Copenhagen V, Denmark, 1560

Public contact

Clinical Trial Information, Genmab A/S, +45 7020 2728, clinicaltrials@genmab.com

Scientific contact

Clinical Trial Information, Genmab A/S, +45 7020 2728, clinicaltrials@genmab.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Dec 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Dec 2017

Global end of trial reached?

Yes

Global end of trial date

13 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

To establish the tolerability of HuMax-TF-ADC dosed three times every four weeks (3q4wk) in a mixed population of patients with specified solid tumors.

Protection of trial subjects

This trial was conducted in compliance with independent ethics committee (IEC)/institutional review board (IRB) and International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines - including Title 21 Part 56 of the United States of America (USA) Code of Federal Regulations (CFR) relating to IRBs and ICH GCP as described in the US Food and Drug Administration (FDA) CFR (21 CFR Part 50, 56, 312), in accordance with applicable regulations regarding clinical safety data management (E2A, E2B(R3)), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9 and E10). In addition, this trial adhered to all local regulatory requirements and requirements for data protection.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Oct 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

Belgium: 13

Country: Number of subjects enrolled

Denmark: 5

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

For the Dose Escalation, participants took part in the trial at 3 sites located in Denmark, the United Kingdom (UK), and the United States (USA) from 30 Nov 2015 until 10 Feb 2017. Cohort Expansion trial was performed at 10 sites located in Belgium, UK, Denmark, and the USA, from 16 Feb 2016 until the last patient visit on 13 Dec 2017.

Screening details

Participants reported to the clinical study site for the eligibility screening within 21 days prior to the first study drug administration. 20 participants were screened and 9 were enrolled across 3 sites in Part 1 Dose Escalation. 51 participants were screened and 24 were enrolled across 10 sites for Part 2 Cohort Expansion.

Period 1 title

Part 1 and Part 2: Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg

Arm description

Tisotumab vedotin 0.9 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 0.9 mg/kg or 1.2 mg/kg intravenous infusion, over a minimum of 30 minutes, 3q4wk.

Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg

Arm description

Tisotumab vedotin 1.2 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3q4wk.

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 0.9 mg/kg or 1.2 mg/kg intravenous infusion, over a minimum of 30 minutes, 3q4wk.

Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian

Arm description

Participants with the indication of ovarian cancer, received Tisotumab vedotin 1.2 mg/kg (the recommended dose for phase II trials [RP2D] from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes, 3q4wk.

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1.2 mg/kg, the RP2D from the Dose Escalation phase, intravenous infusion over a minimum of 30 minutes 3q4wk. Due to the observed severe ocular toxicity, participants received 2.0 mg/kg intravenous infusion over a minimum of 30 minutes, once every 3 weeks (1q3w).

Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical

Arm description

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian

Arm description

Participants with the indication of ovarian cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes, 3q4wk. Due to severe ocular toxicity at the dosing schedule of 1.2 mg/kg 3q4wk, participants switched to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, 1q3w.

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 1.2 mg/kg, the RP2D from the Dose Escalation phase, intravenous infusion over a minimum of 30 minutes 3q4wk. Due to the observed severe ocular toxicity at the dosing schedule of 1.2 mg/kg 3q4wk, participants switched 2.0 mg/kg intravenous infusion over a minimum of 30 minutes, 1q3w.

Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical

Arm description

Participants with the indication of cervical cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes, 3q4wk. Due to severe ocular toxicity at the dosing schedule of 1.2 mg/kg 3q4wk, participants switched to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, 1q3w.

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian

Arm description

Participants with the indication of ovarian cancer received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, 1q3w; the revised dose and schedule due to severe ocular toxicity observed at 1.2 mg/kg 3q4wk.

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 2.0 mg/kg intravenous infusion over a minimum of 30 minutes, 1q3w.

Part 2: Cohort Expansion: Cohort 6 1q3w Cervical

Arm description

Participants with the indication of cervical cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, 1q3w; the revised dose and schedule due to severe ocular toxicity observed at 1.2 mg/kg 3q4wk.

Arm type

Experimental

Investigational medicinal product name

Tisotumab vedotin

Investigational medicinal product code

Other name

HuMax®-TF-ADC

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received 2.0 mg/kg intravenous infusion over a minimum of 30 minutes, 1q3w.

Number of subjects in period 1	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Started	3	6	11	3	1	5	1	3
Completed	0	0	0	0	0	1	0	0
Not completed	3	6	11	3	1	4	1	3
Adverse event, non-fatal	1	-	6	1	-	-	-	-
Patient Choice	-	1	1	-	-	-	1	-
Death	-	-	1	-	-	-	-	-
Investigator Judgment	-	2	-	-	-	-	-	-
Miscellaneous	-	1	-	-	-	-	-	-
Disease Progression	2	2	3	2	1	4	-	3

Baseline characteristics

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Reporting group title

Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg

Reporting group description

Tisotumab vedotin 0.9 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Reporting group title

Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg

Reporting group description

Tisotumab vedotin 1.2 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3q4wk.

Reporting group title

Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 6 1q3w Cervical

Reporting group description

Reporting group values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical	Total
Number of subjects	3	6	11	3	1	5	1	3	33
Age categorical
Units: Subjects
Adults (18-64 years)	0	3	10	3	1	4	1	3	25
From 65-84 years	3	3	1	0	0	1	0	0	8
Age continuous
Units: years
median (full range (min-max))	69.0 (66.0 to 70.0)	61 (38.0 to 71.0)	59.0 (50.0 to 65.0)	55.0 (50.0 to 58.0)	46.0 (46.0 to 46.0)	48.0 (39.0 to 67.0)	59.0 (59.0 to 59.0)	48.0 (30.0 to 60.0)	-
Gender categorical
Units: Subjects
Female	1	4	11	3	1	5	1	3	29
Male	2	2	0	0	0	0	0	0	4
Race
Units: Subjects
White	3	5	10	3	1	5	1	3	31
Asian	0	1	1	0	0	0	0	0	2
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	1	0	0	0	0	0	1
Not Hispanic or Latino	3	6	10	3	1	5	1	3	32
Weight
Units: kg
median (full range (min-max))	80.0 (76.3 to 80.0)	67.5 (48.1 to 85.0)	66.8 (40.0 to 89.6)	55.2 (41.7 to 63.5)	57.8 (57.8 to 57.8)	72.0 (52.8 to 79.3)	96.8 (96.8 to 96.8)	65.3 (60.5 to 65.5)	-
Height
Units: cm
median (full range (min-max))	171.0 (168.0 to 171.4)	162.0 (156.0 to 175.0)	159.0 (154.0 to 174.0)	157.0 (148.0 to 161.0)	160.6 (160.6 to 160.6)	168.0 (159 to 177.8)	170.5 (170.5 to 170.5)	161.0 (156.0 to 162.0)	-
Body Mass Index (BMI)
Units: kg/m^2
median (full range (min-max))	27.4 (26.0 to 28.3)	25.5 (19.8 to 27.8)	26.4 (16.9 to 32.5)	22.4 (16.1 to 29.0)	22.4 (22.4 to 22.4)	24.0 (18.7 to 28.5)	33.3 (33.3 to 33.3)	24.9 (23.3 to 26.9)	-

End points

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Reporting group title

Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg

Reporting group description

Tisotumab vedotin 0.9 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Reporting group title

Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg

Reporting group description

Tisotumab vedotin 1.2 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3q4wk.

Reporting group title

Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 6 1q3w Cervical

Reporting group description

Primary: Part 1: Number of Participants who Experience at Least One Adverse Event (AE)

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End point title

Part 1: Number of Participants who Experience at Least One Adverse Event (AE) ^[1] ^[2]

End point description

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

End point type

Primary

End point timeframe

Part 1 Dose Escalation Phase: Baseline to end of trial, a maximum of 24 weeks (+/- 7 days) post last dose.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	3	6

No statistical analyses for this end point

Primary: Part 2: Number of Participants who Experience at Least One Adverse Event (AE)

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End point title

Part 2: Number of Participants who Experience at Least One Adverse Event (AE) ^[3] ^[4]

End point description

End point type

Primary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, approximately 36 weeks.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	11	3	1	5	0	3

No statistical analyses for this end point

Primary: Part 1: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE)

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End point title

Part 1: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE) ^[5] ^[6]

End point description

End point type

Primary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, maximum of 24 weeks (+/- 7 days) post last dose.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	1	2

No statistical analyses for this end point

Primary: Part 2: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE)

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End point title

Part 2: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE) ^[7] ^[8]

End point description

End point type

Primary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	9	2	0	2	0	1

No statistical analyses for this end point

Primary: Part 1: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events

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End point title

Part 1: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events ^[9] ^[10]

End point description

An infusion-related AE was defined as an AE occurring during infusion where the onset date and time of the event occurred within infusion time (+24 hours), and the event was judged as related to Tisotumab vedotin by the investigator.

End point type

Primary

End point timeframe

Part 1 Dose Escalation: Day 1, Day 8 & Day 15 (+1 day) until end of treatment, up to 48 weeks.

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	2	4

No statistical analyses for this end point

Primary: Part 2: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events

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End point title

Part 2: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events ^[11] ^[12]

End point description

End point type

Primary

End point timeframe

Part 2 Cohort Expansion: Day 1, Day 8 & Day 15 (+1 day) until end of trial, up to 36 weeks.

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	4	2	1	1	0	1

No statistical analyses for this end point

Primary: Part 1: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

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End point title

Part 1: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events ^[13] ^[14]

End point description

End point type

Primary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, a maximum of 24 weeks (+/- 7 days) post last dose.

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	1	3

No statistical analyses for this end point

Primary: Part 2: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

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End point title

Part 2: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events ^[15] ^[16]

End point description

End point type

Primary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	10	2	0	3	0	1

No statistical analyses for this end point

Primary: Part 1: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event

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End point title

Part 1: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event ^[17] ^[18]

End point description

End point type

Primary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, a maximum of 24 weeks (+/- 7 days) post last dose.

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	3	6

No statistical analyses for this end point

Primary: Part 2: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event

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End point title

Part 2: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event ^[19] ^[20]

End point description

End point type

Primary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical tests were performed for this trial
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	9	3	1	5	0	3

No statistical analyses for this end point

Secondary: Part 1: Number of Participants with Markedly Abnormal Laboratory Values

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End point title

Part 1: Number of Participants with Markedly Abnormal Laboratory Values ^[21]

End point description

The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Markedly abnormal laboratory values are defined as any grade >=3 laboratory abnormality events.

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, a maximum of 24 weeks (+/- 7 days) post last dose.

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	0	6

No statistical analyses for this end point

Secondary: Part 2: Number of Participants with Markedly Abnormal Laboratory Values

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End point title

Part 2: Number of Participants with Markedly Abnormal Laboratory Values ^[22]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	5	2	0	3	1	3

No statistical analyses for this end point

Secondary: Part 1: Number of Participants who Experienced a Skin Rash

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End point title

Part 1: Number of Participants who Experienced a Skin Rash ^[23]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, a maximum of 24 weeks (+/- 7 days) post last dose.

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	0	4

No statistical analyses for this end point

Secondary: Part 2: Number of Participants who Experienced a Skin Rash

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End point title

Part 2: Number of Participants who Experienced a Skin Rash ^[24]

End point description

End point type

Secondary

End point timeframe

Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	2	0	1	1	0	1

No statistical analyses for this end point

Secondary: Part 1: Number of Participants who Experienced a Bleeding Event

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End point title

Part 1: Number of Participants who Experienced a Bleeding Event ^[25]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline until end of treatment, up to 48 weeks.

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	3	5

No statistical analyses for this end point

Secondary: Part 2: Number of Participants who Experienced a Bleeding Event

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End point title

Part 2: Number of Participants who Experienced a Bleeding Event ^[26]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	7	3	1	5	0	2

No statistical analyses for this end point

Secondary: Part 1: Number of Participants who Experienced a Neuropathy Event

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End point title

Part 1: Number of Participants who Experienced a Neuropathy Event ^[27]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline until end of treatment, up to 48 weeks.

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	1	3

No statistical analyses for this end point

Secondary: Part 2: Number of Participants who Experienced a Neuropathy Event

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End point title

Part 2: Number of Participants who Experienced a Neuropathy Event ^[28]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	3	1	0	2	0	1

No statistical analyses for this end point

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC) ^[29]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: h*µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	3336 ( 7.3 )	5317 ( 34.6 )
Cycle 1 Day 1	867 ( 17.6 )	1328 ( 48.0 )
Cycle 1 Day 8	1603 ( 16.2 )	2216 ( 11.7 )
Cycle 1 Day 15	789 ( 15.6 )	1411 ( 94.2 )

No statistical analyses for this end point

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC) ^[30]

End point description

9999 has been recorded when there is no data available for the data point. Arms only included 1 participant, no Geometric Coefficient of Variation could be calculated.

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[31]	3 ^[32]
Units: h*µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	2267 ( 24.8 )	1755 ( 19.1 )
Cycle 1 Dose 1	1889 ( 29.3 )	1412 ( 11.9 )
Cycle 1 Dose 2	150 ( 56.2 )	123 ( 85.4 )
Cycle 1 Dose 3	410 ( 26.4 )	204 ( 71.3 )

Notes
[31] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[32] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: AUCinf: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Tisotumab vedotin (HuMax-TF-ADC) ^[33]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline until end of treatment, up to 48 weeks.

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	2	4
Units: h*µg/mL
geometric mean (geometric coefficient of variation)	920 ( 3.6 )	1106 ( 21.3 )

No statistical analyses for this end point

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC) ^[34]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, up to 48 weeks.

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	21.2 ( 14.5 )	30.7 ( 10.1 )
Cycle 1 Day 1	20.2 ( 17.9 )	28.7 ( 12.1 )
Cycle 1 Day 8	20.9 ( 14.1 )	28.0 ( 8.9 )
Cycle 1 Day 15	19.9 ( 11.8 )	26.8 ( 21.6 )

No statistical analyses for this end point

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 2: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC) ^[35]

End point description

9999 has been recorded when there is no data available for the data point. Arms only included 1 participant, no Geometric Coefficient of Variation could be calculated. 9999 has been entered For Arms 'Part 2 Cohort Expansion: Cohort 5 1q3w Ovarian' and 'Part 2 Cohort Expansion: Cohort 6 1q3w Cervical'; as data is only available at Cycle 1 due to changes in dosing schedule. Participants in these arms are only dosed once every 3 weeks (1q3wk).

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[36]	3 ^[37]
Units: µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	28.2 ( 34.5 )	19.5 ( 17.6 )
Cycle 1 Dose 1	28.2 ( 34.5 )	19.5 ( 17.6 )
Cycle 1 Dose 2	1.00 ( 42.0 )	1.13 ( 112.2 )
Cycle 1 Dose 3	3.85 ( 24.5 )	1.85 ( 77.6 )

Notes
[36] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[37] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC) ^[38]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1	5.864 ( 172.022 )	5.061 ( 166.177 )
Cycle 1 Day 1	0.747 ( 11.547 )	0.873 ( 79.228 )
Cycle 1 Day 8	0.717 ( 0 )	0.846 ( 86.481 )
Cycle 1 Day 15	1.141 ( 81.075 )	1.084 ( 73.110 )

No statistical analyses for this end point

Secondary: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC) ^[39]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[40]	3 ^[41]
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1	0.75 ( 68.49 )	0.58 ( 22.85 )
Cycle 1 Dose 1	0.75 ( 68.49 )	0.58 ( 22.85 )
Cycle 1 Dose 2	165.06 ( 75.01 )	106.93 ( 55.38 )
Cycle 1 Dose 3	71.23 ( 24.35 )	80.37 ( 20.24 )

Notes
[40] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[41] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab vedotin (HuMax-TF-ADC) ^[42]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	4
Units: hours
geometric mean (geometric coefficient of variation)	40.45 ( 24.78 )	48.15 ( 16.47 )

No statistical analyses for this end point

Secondary: Part 1: Total Clearance (CL) of Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: Total Clearance (CL) of Tisotumab vedotin (HuMax-TF-ADC) ^[43]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	2	4
Units: mL/h/kg
geometric mean (geometric coefficient of variation)	0.979 ( 3.561 )	1.085 ( 21.476 )

No statistical analyses for this end point

Secondary: Part 1: Apparent Volume of Distribution (Vz) for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: Apparent Volume of Distribution (Vz) for Tisotumab vedotin (HuMax-TF-ADC) ^[44]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	2	4
Units: mL/kg
geometric mean (geometric coefficient of variation)	66.75 ( 6.67 )	75.37 ( 14.89 )

No statistical analyses for this end point

Secondary: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab vedotin (HuMax-TF-ADC)

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End point title

Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab vedotin (HuMax-TF-ADC) ^[45]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	30.0 ( 0 )	30.0 ( 0 )
Cycle 1 Day 8	797.3 ( 22.1 )	1328.5 ( 191.8 )
Cycle 1 Day 15	912.1 ( 23.7 )	989.0 ( 44.3 )

No statistical analyses for this end point

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated) ^[46]

End point description

End point type

Secondary

End point timeframe

Part 1: Baseline to end of treatment (Part 1), up to 48 weeks

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: h*µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	3916 ( 7.3 )	5573 ( 15.0 )
Cycle 1 Day 1	1058 ( 15.0 )	1530 ( 34.7 )
Cycle 1 Day 8	1750 ( 16.2 )	2460 ( 8.5 )
Cycle 1 Day 15	1012 ( 25.7 )	1426 ( 28.6 )

No statistical analyses for this end point

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated) ^[47]

End point description

End point type

Secondary

End point timeframe

Part 2: Baseline to end of trial (Part 2), up to 36 weeks

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[48]	3 ^[49]
Units: h*µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	2660 ( 20.0 )	1948 ( 35.2 )
Cycle 1 Dose 1	1980 ( 24.5 )	460 ( 84.5 )
Cycle 1 Dose 2	299 ( 55.0 )	192 ( 80.9 )
Cycle 1 Dose 3	679 ( 25.7 )	291 ( 89.9 )

Notes
[48] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[49] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Total HuMax-TF (Cojugated and Non-conjugated) ^[50]

End point description

End point type

Secondary

End point timeframe

Part 1: Baseline to end of treatment (Part 1), up to 48 weeks

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	2	6
Units: h*µg/mL
geometric mean (geometric coefficient of variation)	1268 ( 14.4 )	1594 ( 24.6 )

No statistical analyses for this end point

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated) ^[51]

End point description

End point type

Secondary

End point timeframe

Part 1: Baseline to end of treatment (Part 1), up to 48 weeks

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	22.1 ( 9.1 )	31.7 ( 11.9 )
Cycle 1 Day 1	20.3 ( 14.3 )	30.2 ( 11.5 )
Cycle 1 Day 8	21.0 ( 6.3 )	29.2 ( 6.6 )
Cycle 1 Day 15	20.9 ( 12.0 )	29.2 ( 16.2 )

No statistical analyses for this end point

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

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End point title

Part 2: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated) ^[52]

End point description

End point type

Secondary

End point timeframe

Part 2: Baseline to end of trial (Part 2) up to 36 weeks

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[53]	3 ^[54]
Units: µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1	27.5 ( 36.4 )	20.6 ( 18.6 )
Cycle 1 Dose 1	27.5 ( 36.4 )	20.6 ( 18.6 )
Cycle 1 Dose 2	2.00 ( 41.6 )	1.91 ( 105.0 )
Cycle 1 Dose 3	6.39 ( 24.6 )	3.68 ( 66.1 )

Notes
[53] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[54] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated) ^[55]

End point description

End point type

Secondary

End point timeframe

Part 1: Baseline to end of treatment (Part 1), up to 48 weeks

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1	36.445 ( 99.474 )	14.003 ( 117.534 )
Cycle 1 Day 1	0.747 ( 11.547 )	0.893 ( 66.752 )
Cycle 1 Day 8	0.717 ( 0 )	0.869 ( 78.568 )
Cycle 1 Day 15	0.727 ( 4.784 )	0.896 ( 78.665 )

No statistical analyses for this end point

Secondary: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

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End point title

Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated) ^[56]

End point description

End point type

Secondary

End point timeframe

Part 2: Baseline to end of trial (Part 2), up to 36 weeks

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[57]	3 ^[58]
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1	0.86 ( 73.61 )	0.58 ( 22.85 )
Cycle 1 Dose 1	0.86 ( 73.61 )	0.58 ( 22.85 )
Cycle 1 Dose 2	165.06 ( 75.01 )	106 ( 55.38 )
Cycle 1 Dose 3	71.23 ( 24.35 )	80.37 ( 20.24 )

Notes
[57] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[58] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Terminal Phase Elimination Half-life (T1/2) for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 1: Terminal Phase Elimination Half-life (T1/2) for Total HuMax-TF (Cojugated and Non-conjugated) ^[59]

End point description

End point type

Secondary

End point timeframe

Part 1: Baseline to end of treatment (Part 1), up to 48 weeks

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: hours
geometric mean (geometric coefficient of variation)	49.56 ( 17.35 )	49.34 ( 19.18 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Total Clearance (CL) of Total HuMax-TF (Conjugated and Non-conjugated)

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End point title

Part 1 and Part 2: Total Clearance (CL) of Total HuMax-TF (Conjugated and Non-conjugated) ^[60]

End point description

CL could not be estimated for Part 1 or Part 2 participants due to insufficient samples taken.

End point type

Secondary

End point timeframe

Part 1 & Part 2: Baseline to end of trial (Part 1 & Part 2), approximately 21 months

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: CL could not be calculated, therefore no data is present.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	0 ^[61]	0 ^[62]	0 ^[63]	0 ^[64]
Units: mL/h/kg
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )

Notes
[61] - CL could not be estimated.
[62] - CL could not be estimated.
[63] - CL could not be estimated.
[64] - CL could not be estimated.

No statistical analyses for this end point

Secondary: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Total HuMax-TF (Conjugated and Non-conjugated)

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End point title

Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Total HuMax-TF (Conjugated and Non-conjugated) ^[65]

End point description

End point type

Secondary

End point timeframe

Part 1: Baseline to end of treatment, up to 48 weeks

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	150.0 ( 0 )	150.0 ( 0 )
Cycle 1 Day 8	1273.1 ( 23.4 )	1252.2 ( 53.3 )
Cycle 1 Day 15	1625.1 ( 24.4 )	1863.8 ( 46.6 )

No statistical analyses for this end point

Secondary: Part 1 & Part 2: Apparent Volume of Distribution (Vz) for Total HuMax-TF (Cojugated and Non-conjugated)

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End point title

Part 1 & Part 2: Apparent Volume of Distribution (Vz) for Total HuMax-TF (Cojugated and Non-conjugated) ^[66]

End point description

Vz/F could not be estimated for Part 1 or Part 2 participants due to insufficient samples taken.

End point type

Secondary

End point timeframe

Part 1 & Part 2: Baseline to end of trial (Part 1 & Part 2), approximately 21 months

Notes
[66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Vz could not be calculated, therefore no data is present.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	0 ^[67]	0 ^[68]	0 ^[69]	0 ^[70]
Units: mL/kg
geometric mean (geometric coefficient of variation)	( )	( )	( )	( )

Notes
[67] - Vz/F could not be estimated.
[68] - Vz/F could not be estimated.
[69] - Vz/F could not be estimated.
[70] - Vz/F could not be estimated.

No statistical analyses for this end point

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for free toxin (MMAE)

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End point title

Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for free toxin (MMAE) ^[71]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	885 ( 27.1 )	968 ( 59.7 )
Cycle 1 Day 1	185 ( 48.1 )	185 ( 75.3 )
Cycle 1 Day 8	180 ( 14.1 )	236 ( 75.5 )
Cycle 1 Day 15	506 ( 25.3 )	520 ( 51.3 )

No statistical analyses for this end point

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for free toxin (MMAE)

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End point title

Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for free toxin (MMAE) ^[72]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[73]	3 ^[74]
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	920 ( 74.5 )	1049 ( 89.4 )
Cycle 1 Dose 1	439 ( 69.3 )	393 ( 100.0 )
Cycle 1 Dose 2	378 ( 121.3 )	366 ( 77.9 )
Cycle 1 Dose 3	713 ( 49.9 )	494 ( 121.7 )

Notes
[73] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[74] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for free toxin (MMAE)

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End point title

Part 1: Cmax: Maximum Observed Plasma Concentration for free toxin (MMAE) ^[75]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	2.76 ( 23.7 )	2.88 ( 52.4 )
Cycle 1 Day 1	1.46 ( 54.7 )	1.38 ( 78.4 )
Cycle 1 Day 8	1.18 ( 19.8 )	1.54 ( 75.4 )
Cycle 1 Day 15	2.76 ( 23.7 )	2.88 ( 52.4 )

No statistical analyses for this end point

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for free toxin (MMAE)

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End point title

Part 2: Cmax: Maximum Observed Plasma Concentration for free toxin (MMAE) ^[76]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[77]	3 ^[78]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	3.9 ( 97.0 )	3.6 ( 101.4 )
Cycle 1 Dose 1	1.9 ( 110.5 )	1.5 ( 80.4 )
Cycle 1 Dose 2	2.47 ( 136.4 )	2.50 ( 81.1 )
Cycle 1 Dose 3	3.78 ( 81.6 )	3.23 ( 125.0 )

Notes
[77] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n = 6
[78] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for free toxin (MMAE)

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End point title

Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for free toxin (MMAE) ^[79]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[79] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1	392.024 ( 3.256 )	373.366 ( 6.290 )
Cycle 1 Day 1	44.568 ( 114.567 )	32.001 ( 125.788 )
Cycle 1 Day 8	10.354 ( 165.509 )	20.837 ( 106.094 )
Cycle 1 Day 15	54.511 ( 20.424 )	32.537 ( 63.879 )

No statistical analyses for this end point

Secondary: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for free toxin (MMAE)

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End point title

Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for free toxin (MMAE) ^[80]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical
Number of subjects analysed	11 ^[81]	3 ^[82]
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1	307.05 ( 36.52 )	410.61 ( 3.82 )
Cycle 1 Dose 1	160.56 ( 5.66 )	162.19 ( 1.71 )
Cycle 1 Dose 2	164.82 ( 56.71 )	106.93 ( 55.38 )
Cycle 1 Dose 3	78.37 ( 50.26 )	80.37 ( 20.24 )

Notes
[81] - Cycle 1 Dose 2: n = 9 Cycle 1 Dose 3: n - 6
[82] - Cycle 1 Dose 3: n = 2

No statistical analyses for this end point

Secondary: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for free toxin (MMAE)

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End point title

Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for free toxin (MMAE) ^[83]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[83] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: pg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	12.50 ( 0 )	12.50 ( 0 )
Cycle 1 Day 8	853.42 ( 22.93 )	1061.28 ( 87.81 )
Cycle 1 Day 15	1013.22 ( 14.47 )	1384.29 ( 83.43 )

No statistical analyses for this end point

Secondary: Part 1: Number of Participants with a Positive Anti-drug antibody (ADA) Immunogenicity Result

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End point title

Part 1: Number of Participants with a Positive Anti-drug antibody (ADA) Immunogenicity Result ^[84]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of trial, up to 48 weeks.

Notes
[84] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	0	0

No statistical analyses for this end point

Secondary: Part 2: Number of Participants with a Positive Anti-drug antibody (ADA) Immunogenicity Result

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End point title

Part 2: Number of Participants with a Positive Anti-drug antibody (ADA) Immunogenicity Result ^[85]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[85] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Part 1: Number of Patients who experienced anti-tumor activity measured by tumor shrinkage

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End point title

Part 1: Number of Patients who experienced anti-tumor activity measured by tumor shrinkage ^[86]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[86] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants	1	3

No statistical analyses for this end point

Secondary: Part 2: Anti-tumor Activity Measured by Percentage of Change in Sum of Lesion Measurements

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End point title

Part 2: Anti-tumor Activity Measured by Percentage of Change in Sum of Lesion Measurements ^[87]

End point description

9999 has been used when there is no data. As the arm only includes 1 participants, there is no Standard Deviation data to enter.

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[87] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: percent
arithmetic mean (standard deviation)	-17.34 ( 43.388 )	32.78 ( 83.933 )	-63.27 ( 9999 )	0.74 ( 21.877 )	0 ( 9999 )	11.76 ( 27.658 )

No statistical analyses for this end point

Secondary: Part 1: Response Evaluation based on PSA (Prostate specific antigen [Prostate Cancer]): Percentage of Change from Baseline to End of Study

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End point title

Part 1: Response Evaluation based on PSA (Prostate specific antigen [Prostate Cancer]): Percentage of Change from Baseline to End of Study ^[88]

End point description

9999 has been recorded when there is no data to enter for a data point. As only 1 participant is included in the data set, there is no Standard Deviation.

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline until end of treatment, up to 48 weeks.

Notes
[88] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	2	1
Units: percent
arithmetic mean (standard deviation)	23.42 ( 61.686 )	12.97 ( 9999 )

No statistical analyses for this end point

Secondary: Part 1: Response Evaluation based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial cancer]): Percentage of Change from Baseline to End of Study

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End point title

Part 1: Response Evaluation based on CA125 (Cancer Antigen 125 [Ovarian and Endometrial cancer]): Percentage of Change from Baseline to End of Study ^[89]

End point description

9999 has been recorded when there is no data to enter for a data point. Only 1 participant is included in the arm, so no Standard Deviation could be calculated.

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[89] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	0 ^[90]	1
Units: percent
arithmetic mean (standard deviation)	( )	186.21 ( 9999 )

Notes
[90] - No participants with the indication of Ovarian or Endometrial Cancer had results at the End of Study

No statistical analyses for this end point

Secondary: Part 2: Response Evaluation based on CA125 (Ovarian and Endometrial cancer): Percentage of Change from Baseline to End of Study

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End point title

Part 2: Response Evaluation based on CA125 (Ovarian and Endometrial cancer): Percentage of Change from Baseline to End of Study ^[91]

End point description

9999 has been recorded when there is no data to recorded for a data point. As only 1 participant was included in the arm, no Standard Deviation could be calculated.

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[91] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	8	0 ^[92]	1	0 ^[93]	0 ^[94]	0 ^[95]
Units: percent
arithmetic mean (standard deviation)	-31.75 ( 36.235 )	( )	-32.50 ( 9999 )	( )	( )	( )

Notes
[92] - CA125 was assessed in patients with ovarian or endometrial cancer only.
[93] - CA125 was assessed in patients with ovarian or endometrial cancer only.
[94] - No participants with the indication of Ovarian Cancer had results at End of Study.
[95] - CA125 was assessed in patients with ovarian or endometrial cancer only.

No statistical analyses for this end point

Secondary: Part 1: Best Overall Response (OR)

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End point title

Part 1: Best Overall Response (OR) ^[96]

End point description

Best OR (by investigators assessment) was the best response recorded from the start of the treatment until disease progression or death. Complete response: the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. Based on non-target lesions, complete response was defined as disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). Partial response (PR): ≥ 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LDs. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of LDs while in trial. Based on non-target lesions, stable disease was defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment (Part 1), up to 48 weeks

Notes
[96] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants
Complete Response	0	0
Partial Response	0	1
Stable Disease	2	3
Progressive Disease	1	1
Not Evaluable	0	1

No statistical analyses for this end point

Secondary: Part 2: Best Overall Response (OR)

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End point title

Part 2: Best Overall Response (OR) ^[97]

End point description

Best OR (by investigators assessment) was the best response recorded from the start of the treatment until disease progression or death. Complete response: the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. Based on non-target lesions, complete response was defined as disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). Partial response (PR): ≥ 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LDs. Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of LDs while in trial. Based on non-target lesions, stable disease was defined as persistence of 1 or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial (Part 2), up to 36 weeks

Notes
[97] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No formal statistical tests were performed for this trial

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants
Complete Response	0	0	0	0	0	0
Partial Response	3	1	1	2	0	0
Stable Disease	3	0	0	2	0	2
Progressive Disease	2	2	0	1	1	1
Not Evaluable	3	0	0	0	0	0

No statistical analyses for this end point

Secondary: Part 1: Number of Participants who experienced Disease Control

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End point title

Part 1: Number of Participants who experienced Disease Control ^[98]

End point description

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: 6, 12, 24 and 36 weeks post first dose.

Notes
[98] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: Participants
6 Weeks	2	3
12 Weeks	0	0
24 Weeks	0	0
36 Weeks	0	0

No statistical analyses for this end point

Secondary: Part 2: Number of Participants who experienced Disease Control

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End point title

Part 2: Number of Participants who experienced Disease Control ^[99]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: 6, 12, 24 and 36 weeks post first dose.

Notes
[99] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: Participants
6 Weeks	6	1	1	4	0	2
12 Weeks	2	1	1	2	0	1
24 Weeks	0	0	0	1	0	0
36 Weeks	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Part 1: Proportion of Patients with Progression Free Survival

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End point title

Part 1: Proportion of Patients with Progression Free Survival ^[100]

End point description

Based on target lesions, progressive disease was defined as ≥ 20% (and ≥ 5 m m) increase in the sum of the LDs of target lesions, taking as reference the smallest sum of the target LDs recorded while in trial or the appearance of 1 or more new lesions. Based on non-target lesions, progressive disease was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. The proportion of patients with PFS will be summarized using Kaplan-Meier estimates.

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: 12, 24, 36, 48 and 60 Weeks Post first dose.

Notes
[100] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	3	6
Units: percentage of participants
number (not applicable)
12 Weeks	50	67
24 Weeks	0	67
36 Weeks	0	67
48 Weeks	0	67
60 Weeks	0	67

No statistical analyses for this end point

Secondary: Part 2: Proportion of Patients with Progression Free Survival

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End point title

Part 2: Proportion of Patients with Progression Free Survival ^[101]

End point description

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: 12, 24 and 36 weeks post first dose.

Notes
[101] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	11	3	1	5	1	3
Units: percentage of participants
number (not applicable)
12 Weeks	39	33	100	60	0	33
24 Weeks	39	33	0	20	0	0
36 Weeks	39	33	0	20	0	0

No statistical analyses for this end point

Secondary: Part 1: Duration of Response

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End point title

Part 1: Duration of Response ^[102]

End point description

Duration of response was defined as as the number of days from the first documentation of objective tumor response (complete response [CR] or partial response [PR]) to the date of first progressive disease (PD) or death. Duration of Response could not be estimated as participants with a confirmed response were discontinued due to toxicity or other reason different from PD or death.

End point type

Secondary

End point timeframe

Part 1 Dose Escalation: Baseline to end of treatment, up to 48 weeks.

Notes
[102] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 1 is displayed for this endpoint.

End point values	Part 1: Dose Escalation: Cohort 1 3q4wk 0.9 mg/kg	Part 1: Dose Escalation: Cohort 2 3q4wk 1.2 mg/kg
Number of subjects analysed	0 ^[103]	0 ^[104]
Units: Weeks
median (confidence interval 95%)	( to )	( to )

Notes
[103] - Duration of response could not be calculated due to insufficient number of participants.
[104] - 1 participant was responder but DOR was censored, therefore duration of response was not calculated

No statistical analyses for this end point

Secondary: Part 2: Duration of Response

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End point title

Part 2: Duration of Response ^[105]

End point description

Duration of response was defined as as the number of days from the first documentation of objective tumor response (CR or PR) to the date of first PD or death. Duration of Response could not be estimated as patients with a confirmed response were discontinued due to toxicity or other reason different from PD or death.

End point type

Secondary

End point timeframe

Part 2 Cohort Expansion: Baseline to end of trial, up to 36 weeks.

Notes
[105] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Study was conducted in 2 parts; Part 1 Dose Escalation and Part 2 Cohort Expansion. Only data for Part 2 is displayed for this endpoint.

End point values	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Number of subjects analysed	0 ^[106]	0 ^[107]	0 ^[108]	0 ^[109]	0 ^[110]	0 ^[111]
Units: Weeks
number (not applicable)

Notes
[106] - Duration of response could not be calculated as participants discontinued.
[107] - Duration of response could not be calculated as participants discontinued.
[108] - Duration of response could not be calculated as participants discontinued.
[109] - Duration of response could not be calculated as participants discontinued.
[110] - Duration of response could not be calculated as participants discontinued.
[111] - Duration of response could not be calculated as participants discontinued.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline to End of Trial (Part 1 &2), approximately 21 Months.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Part 1: Dose Escalation: Cohort 1 0.9mg/kg

Reporting group description

Tisotumab vedotin 0.9 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Reporting group title

Part 1: Dose Escalation: Cohort 2 1.2 mg/kg

Reporting group description

Tisotumab vedotin 1.2 mg/kg was administered as an intravenous infusion, over a minimum of 30 minutes, 3 times every 4 weeks (3q4wk).

Reporting group title

Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical

Reporting group description

Reporting group title

Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian

Reporting group description

Participants with the indication of ovarian cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk). Due to severe ocular toxicity, participants continued to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w).

Reporting group title

Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical

Reporting group description

Participants with the indication of cervical cancer, received Tisotumab vedotin 1.2 mg/kg (RP2D from the Dose Escalation part), administered as an intravenous infusion, over a minimum of 30 minutes 3 times every 4 weeks (3q4wk). Due to severe ocular toxicity, participants continued to receive Tisotumab vedotin at 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w).

Reporting group title

Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian

Reporting group description

Participants with the indication of ovarian cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w).

Reporting group title

Part 2: Cohort Expansion: Cohort 6 1q3w Cervical

Reporting group description

Participants with the indication of cervical cancer, received Tisotumab vedotin 2.0 mg/kg, administered as an intravenous infusion, over a minimum of 30 minutes, once every 3 weeks (1q3w).

Serious adverse events	Part 1: Dose Escalation: Cohort 1 0.9mg/kg	Part 1: Dose Escalation: Cohort 2 1.2 mg/kg	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	2 / 6 (33.33%)	9 / 11 (81.82%)	2 / 3 (66.67%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
number of deaths (all causes)	0	0	1	0	0	0	0	0
number of deaths resulting from adverse events	0	0	1	0	0	0	0	0
Cardiac disorders
Atrial flutter
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Symblepharon
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 11 (36.36%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nauea
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic pseudo-obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Conjunctivitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 11 (27.27%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	3 / 3	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1: Dose Escalation: Cohort 1 0.9mg/kg	Part 1: Dose Escalation: Cohort 2 1.2 mg/kg	Part 2: Cohort Expansion: Cohort 1 3q4wk Ovarian	Part 2: Cohort Expansion: Cohort 2 3q4wk Cervical	Part 2: Cohort Expansion: Cohort 3 3q4wk - 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 4 3q4wk - 1q3w Cervical	Part 2: Cohort Expansion: Cohort 5 1q3w Ovarian	Part 2: Cohort Expansion: Cohort 6 1q3w Cervical
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	6 / 6 (100.00%)	11 / 11 (100.00%)	3 / 3 (100.00%)	1 / 1 (100.00%)	5 / 5 (100.00%)	0 / 1 (0.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Vascular disorders
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 3 (66.67%)	2 / 6 (33.33%)	6 / 11 (54.55%)	1 / 3 (33.33%)	1 / 1 (100.00%)	4 / 5 (80.00%)	0 / 1 (0.00%)	2 / 3 (66.67%)
occurrences all number	2	2	8	1	1	6	0	3
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	1	0	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	3 / 3 (100.00%)	5 / 6 (83.33%)	7 / 11 (63.64%)	1 / 3 (33.33%)	1 / 1 (100.00%)	3 / 5 (60.00%)	0 / 1 (0.00%)	2 / 3 (66.67%)
occurrences all number	4	5	8	1	1	3	0	5
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	1	1	0	0
Cough
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	2	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Laryngeal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Nasal dryness
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Pulmonary haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	0	0	1
Sinus congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	1	0	0
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	2	0	0	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Vital dye staining cornea present
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Urine output increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Injury, poisoning and procedural complications
Radiation proctitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Nervous system disorders
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	4 / 6 (66.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	4	1	0	0	1	0	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	1	0	0	2	0	1
Headache
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	1	0	0
Polyneuropathy
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 11 (9.09%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	1	0	0	0	0
Dizziness
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 11 (18.18%)	1 / 3 (33.33%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	4	2	0	2	0	2
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	3 / 5 (60.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	7	0	0	3	0	1
Blepharitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	0	1	0	1
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2	0	0	0	0	1
Keratitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	4	0	0
Meibomianitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	1
Lacrimation increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Symblepharon
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0
Punctate keratitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Episcleritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Keratopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Ocular hyperaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Ulcerative keratitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	3 / 11 (27.27%)	1 / 3 (33.33%)	0 / 1 (0.00%)	4 / 5 (80.00%)	0 / 1 (0.00%)	2 / 3 (66.67%)
occurrences all number	0	3	4	1	0	6	0	2
Constipation
subjects affected / exposed	0 / 3 (0.00%)	4 / 6 (66.67%)	5 / 11 (45.45%)	1 / 3 (33.33%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	5	5	1	0	2	0	1
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 6 (50.00%)	4 / 11 (36.36%)	0 / 3 (0.00%)	1 / 1 (100.00%)	3 / 5 (60.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	4	0	1	4	0	0
Nausea
subjects affected / exposed	2 / 3 (66.67%)	2 / 6 (33.33%)	5 / 11 (45.45%)	1 / 3 (33.33%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	2	6	1	1	1	0	0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 11 (36.36%)	1 / 3 (33.33%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	6	1	0	1	0	1
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	1
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dry mouth
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Lip ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	1 / 1 (100.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Melaena
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Rectal discharge
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0
Tongue blistering
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	5 / 11 (45.45%)	1 / 3 (33.33%)	1 / 1 (100.00%)	3 / 5 (60.00%)	0 / 1 (0.00%)	2 / 3 (66.67%)
occurrences all number	0	1	5	1	1	3	0	2
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	1 / 3 (33.33%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	1	1	1	0	0
Rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	1	0	0	2	0	1
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	1	0	0	0	0	1
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	2 / 3 (66.67%)
occurrences all number	0	4	0	1	0	0	0	4
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Cystitis noninfective
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	3	0	0	1	0	2
Myalgia
subjects affected / exposed	1 / 3 (33.33%)	3 / 6 (50.00%)	3 / 11 (27.27%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	3	3	1	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	1	0	0	1	0	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	2	0	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	2 / 3 (66.67%)	6 / 6 (100.00%)	5 / 11 (45.45%)	0 / 3 (0.00%)	0 / 1 (0.00%)	3 / 5 (60.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	2	12	6	0	0	6	0	1
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 11 (9.09%)	1 / 3 (33.33%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	1	1	1	1	0	2
Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	2	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	0	0	0	1
Cystitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Rash pustular
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1
Rhinitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 11 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Escherichia vaginitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Influenza
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Pneumonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 3 (66.67%)	3 / 6 (50.00%)	5 / 11 (45.45%)	1 / 3 (33.33%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	4	5	1	1	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	3 / 5 (60.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	3	0	0	3	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 11 (18.18%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	2	0	0	1	0	0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0
Cell death
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 11 (9.09%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Hyperlipidaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 11 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Jul 2016

The main purpose of Protocol Amendment 1 was to add a Cohort Expansion part to the existing Dose Escalation part of the trial. The Cohort Expansion part of the trial was a phase II trial designed to gather additional safety, tolerability, PK and anti-tumor activity data by exposing patients to the R2PD established in the Dose Escalation part. For the Cohort Expansion part, additional phase II sites were planned to be opened in the ongoing countries (Denmark, the UK and the USA) and in Hungary and Belgium. Other main changes included the following; the international nonproprietary name (INN)/chemical name for HuMax-TF-ADC, tisotumab vedotin was added to the protocol as appropriate. Updated information from clinical experience with tisotumab vedotin in the GEN701 trial and the Dose Escalation part of GEN702 was added to the protocol. Addition of mitigation plan for ocular events. Events of conjunctivitis were not included in the Investigator’s Brochure or the Subject ICF for tisotumab vedotin at that time. The protocol was updated to ensure that investigators and patients were informed about the event, and the risk was sufficiently mitigated in the trial going forward. Exclusion criterion #9 was modified to include specifications on blood transfusion and/or erythropoietin use. A 40-day washout period combined with a requirement for no residual check-point inhibitor related symptoms of autoimmune toxicity was added to the protocol. This was based on input provided by investigators and literature review evaluated to accommodate both feasibility of inclusion of patients in the trial as well as patient safety. For the Cohort Expansion part of the trial, the DMC would not hold preplanned meetings but would convene in the event of any safety signals.

27 Oct 2016

Additional information indicating a need for further risk mitigation activities for events of conjunctivitis was reported to the sponsor. The sponsor, in collaboration with external ophthalmologists, evaluated the need for additional risk mitigation activities. The main purpose of Protocol Amendment 2 was to modify the evaluation and mitigation plan for ocular events, as follows: 1) Baseline ophthalmological assessment as well as ongoing ophthalmological assessment of all patients. 2) Exclusion criteria added concerning patients with active ocular surface disease as well as patients with a medical history of cicatricial conjunctivitis. 3) All patients with ocular symptoms had to undergo prompt ophthalmological assessment. 4) More elaborated criteria for holding dose, reducing dose and treatment withdrawal. 5) Optional treatment guidance for ophthalmological treatment of events of conjunctivitis included for information to the treating ophthalmologist. The Investigator’s Brochure and the ICF were updated accordingly. The above-mentioned activities had been discussed and agreed with the DMC for both the GEN701 and GEN702 trials. The new information was not considered to change the overall benefit-risk profile of tisotumab vedotin. Also in Protocol Amendment 2, some inclusion and exclusion criteria were reworded for clarification and/or to adapt to current experience or standard practice.

22 Dec 2016

This was an urgent safety amendment. One CTCAE grade 3 event of conjunctivitis had already been reported in the GEN702 trial. Following the cut-off date of 31 May 2016, three additional CTCAE grade 3 events of conjunctivitis and one CTCAE grade 4 event of keratitis had been reported with tisotumab vedotin. The purpose of Protocol Amendment 3 was to update this information in the protocol and to modify the dose modification and mitigation plan for ocular events accordingly, including mandatory preventive eye therapy. In addition, reduced dose could be administered in accordance with the added mitigation strategies or at the discretion of the treating physician, and after consultation and agreement by the sponsor Medical Officer.

06 Jul 2017

This was an urgent safety amendment. The DMC and the Genmab Safety Committee assessed the safety profile observed to date and agreed that patients should not continue treatment at the 1.2 mg/kg 3q4w dose/schedule and supported the following change in dose: the treatment schedule consisting of 2.0 mg/kg dose 1q3w determined from GEN701, which had demonstrated a favorable benefit risk assessment for patients with advanced/metastatic tumors. Additional measurements were also implemented to the mitigation plan for ocular AEs, and a requirement of urgent reporting of non-serious grade 2 ocular events was added. As a consequence of this Protocol Amendment 4, the patient and the investigator had to review continued participation in the GEN702 trial together. If the patient decided to continue all future administrations, the patient would be dosed at 2.0 mg/kg 1q3w, regardless of the prior dose(s) administered. The next dose of tisotumab vedotin could not be administered until at least 21 days had elapsed since the last administration. The sites were also provided with specific instructions for operational handling of switching patients from the 3q4w to the 1q3w dosing scheme. The patients had to sign a new ICF.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Dose-escalating and cohort expansion safety trial of tissue factor specific antibody drug conjugate tisotumab vedotin (HuMax®-TF-ADC) in patients with locally advanced and/or metastatic solid tumors known to express tissue factor

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Number of Participants who Experience at Least One Adverse Event (AE)

Primary: Part 1: Number of Participants who Experience at Least One Adverse Event (AE)

Primary: Part 2: Number of Participants who Experience at Least One Adverse Event (AE)

Primary: Part 2: Number of Participants who Experience at Least One Adverse Event (AE)

Primary: Part 1: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE)

Primary: Part 1: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE)

Primary: Part 2: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE)

Primary: Part 2: Number of Participants who Experienced at Least One or More Serious Adverse Event (SAE)

Primary: Part 1: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events

Primary: Part 1: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events

Primary: Part 2: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events

Primary: Part 2: Number of Participants who Experienced at Least One or More Infusion-related Adverse Events

Primary: Part 1: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

Primary: Part 1: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

Primary: Part 2: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

Primary: Part 2: Number of Participants who Experienced at Least One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3 Adverse Events

Primary: Part 1: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event

Primary: Part 1: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event

Primary: Part 2: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event

Primary: Part 2: Number of Participants who Experienced at Least One or More Treatment-related Adverse Event

Secondary: Part 1: Number of Participants with Markedly Abnormal Laboratory Values

Secondary: Part 1: Number of Participants with Markedly Abnormal Laboratory Values

Secondary: Part 2: Number of Participants with Markedly Abnormal Laboratory Values

Secondary: Part 2: Number of Participants with Markedly Abnormal Laboratory Values

Secondary: Part 1: Number of Participants who Experienced a Skin Rash

Secondary: Part 1: Number of Participants who Experienced a Skin Rash

Secondary: Part 2: Number of Participants who Experienced a Skin Rash

Secondary: Part 2: Number of Participants who Experienced a Skin Rash

Secondary: Part 1: Number of Participants who Experienced a Bleeding Event

Secondary: Part 1: Number of Participants who Experienced a Bleeding Event

Secondary: Part 2: Number of Participants who Experienced a Bleeding Event

Secondary: Part 2: Number of Participants who Experienced a Bleeding Event

Secondary: Part 1: Number of Participants who Experienced a Neuropathy Event

Secondary: Part 1: Number of Participants who Experienced a Neuropathy Event

Secondary: Part 2: Number of Participants who Experienced a Neuropathy Event

Secondary: Part 2: Number of Participants who Experienced a Neuropathy Event

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 2: Tmax: Time to Reach the Maximum Plasma Concentration for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Terminal Phase Elimination Half-life (T1/2) for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Total Clearance (CL) of Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Total Clearance (CL) of Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Apparent Volume of Distribution (Vz) for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Apparent Volume of Distribution (Vz) for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic for Tisotumab vedotin (HuMax-TF-ADC)

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 1: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 2: AUC0-t: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of Last Quantifiable Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 1: AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 1: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Secondary: Part 2: Cmax: Maximum Observed Plasma Concentration for Total HuMax-TF (Conjugated and Non-conjugated)

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Secondary: Part 1: Tmax: Time to Reach the Maximum Plasma Concentration for Total HuMax-TF (Cojugated and Non-conjugated)

Clinical Trial Results:
Dose-escalating and cohort expansion safety trial of tissue factor specific antibody drug conjugate tisotumab vedotin (HuMax®-TF-ADC) in patients with locally advanced and/or metastatic solid tumors known to express tissue factor