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Clinical Trial Results:
A Phase 1/2 Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma.

Summary
EudraCT number	2011-001240-29
Trial protocol	DE GB NL IT ES
Global end of trial date	12 Apr 2018

Results information
Results version number	v1(current)
This version publication date	27 Oct 2018
First version publication date	27 Oct 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

C25002

ISRCTN number

US NCT number

NCT01492088

WHO universal trial number (UTN)

U1111-1158-2613

Other trial identifiers

RNEC: 133300410A0384, CCMO: NL38209.078.11

Sponsor organisation name

Takeda Oncology

Sponsor organisation address

40 Landsdowne Street, Cambridge, MA, United States, 02139

Public contact

Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com

Scientific contact

Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000980-PIP01-10

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?

Yes

Analysis stage

Final

Date of interim/final analysis

12 Apr 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Apr 2018

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to assess the safety and pharmacokinetics, and determine the pediatric maximum tolerated dose and/or or recommended phase 2 dose of brentuximab vedotin.

Protection of trial subjects

All study participants or their guardians were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Apr 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Regulatory reason

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

Spain: 4

Country: Number of subjects enrolled

Mexico: 1

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

Participants took part in the study at 12 investigative sites in United States, France, Germany, Netherlands, United Kingdom, Italy, Spain and Mexico from 16-April-2012 to 12-April-2018.

Screening details

Participants with diagnosis of relapsed or refractory (r/r) sALCL/HL were enrolled to receive brentuximab vedotin 1.4-1.8 mg/kg, intravenous infusion on Day 1 of every 21-day cycle for up to 16 cycles. Treatment beyond 16 cycles was permitted at joint discretion of sponsor and investigator for participants experiencing continued clinical benefit.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Brentuximab vedotin 1.4 mg/kg: Phase 1

Arm description

Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Brentuximab vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion, Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Brentuximab vedotin Intravenous Infusion

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only

Arm description

Participants with r/r HL received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

Arm type

Experimental

Investigational medicinal product name

Brentuximab vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion, Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Brentuximab vedotin Intravenous Infusion

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only

Arm description

Participants with r/r systemic anaplastic large-cell lymphoma (sALCL) received brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

Arm type

Experimental

Investigational medicinal product name

Brentuximab vedotin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion, Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Brentuximab vedotin Intravenous Infusion

Number of subjects in period 1	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Started	3	16	17
Completed	0	2	3
Not completed	3	14	14
Completed Post Treatment Followup (PTFU)	2	-	1
Death	1	6	2
Alive at Last Follow-up	-	6	11
Withdrawal by Patient	-	2	-

Baseline characteristics

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Reporting group title

Brentuximab vedotin 1.4 mg/kg: Phase 1

Reporting group description

Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

Reporting group title

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only

Reporting group description

Reporting group title

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only

Reporting group description

Reporting group values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only	Total
Number of subjects	3	16	17	36
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	2	10	12
Adults (18-64 years)	3	14	7	24
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	14.7 ( 1.15 )	14.5 ( 2.68 )	11.5 ( 3.18 )	-
Sex: Female, Male
Units: Subjects
Female	1	7	3	11
Male	2	9	14	25
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	4	4
Not Hispanic or Latino	3	14	12	29
Unknown or Not Reported	0	2	1	3
Race/Ethnicity, Customized
Units: Subjects
White	2	13	16	31
Asian	1	0	0	1
Other	0	2	1	3
Not Reported	0	1	0	1
Region of Enrollment
Units: Subjects
United States	2	1	1	4
France	0	2	0	2
Germany	0	4	1	5
Netherlands	0	1	2	3
United Kingdom	0	1	2	3
Italy	1	7	6	14
Spain	0	0	4	4
Mexico	0	0	1	1
Height
Units: cm
arithmetic mean (standard deviation)	167.17 ( 10.865 )	165.31 ( 14.350 )	149.54 ( 17.783 )	-
Weight
Units: kg
arithmetic mean (standard deviation)	53.10 ( 9.924 )	57.85 ( 17.539 )	42.16 ( 15.162 )	-
Body Surface Area
Units: m^2
arithmetic mean (standard deviation)	1.562 ( 0.0967 )	1.617 ( 0.2938 )	1.313 ( 0.3103 )	-

End points

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Reporting group title

Brentuximab vedotin 1.4 mg/kg: Phase 1

Reporting group description

Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

Reporting group title

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only

Reporting group description

Reporting group title

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only

Reporting group description

Subject analysis set title

Brentuximab vedotin 1.8 mg/kg: Phase 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

Subject analysis set title

Brentuximab vedotin 1.8 mg/kg: Phase 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle starting from Cycle 2 until there was evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

Subject analysis set title

Brentuximab vedotin 1.8 mg/kg: Phase 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Brentuximab vedotin 1.8 mg/kg: Phase 1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1)

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End point title

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1) ^[1] ^[2]

End point description

An 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 treatment. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. AE severity was graded according to NCI CTCAE version 4.03. Safety population is defined as all participants who received at least 1 dose of study drug. Participants enrolled in Phase 1 of study were evaluated for this endpoint.

End point type

Primary

End point timeframe

From the first dose through 30 days after the last dose of study medication (Up to 15 months)

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: Only descriptive statistics were planned for this endpoint.
[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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	9
Units: participants
TEAE	3	9
SAE	0	4

No statistical analyses for this end point

Primary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1)

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End point title

Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1) ^[3] ^[4]

End point description

Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population is defined as all participants who received at least 1 dose of study drug. Participants enrolled in Phase 1 of study were evaluated for this endpoint.

End point type

Primary

End point timeframe

From the first dose through 30 days after the last dose of study medication (Up to 15 months)

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: Only descriptive statistics were planned for this endpoint.
[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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	9
Units: participants
Gamma-glutamyltransferase increased	0	1
Transaminases increased	0	1
Lymphocyte count decreased	1	1
Neutrophil count decreased	0	1
Blood bicarbonate decreased	0	1
Weight decreased	0	1
Hypocalaemia	0	2
Hyperuricaemia	0	1

No statistical analyses for this end point

Primary: Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1)

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End point title

Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1) ^[5] ^[6]

End point description

Vital signs measurements included supine (after 3-5 minutes in this position) and standing (after 3-5 minutes in this position) measurements of diastolic and systolic blood pressure, heart rate, and oral temperature. Safety population is defined as all participants who received at least 1 dose of study drug.

End point type

Primary

End point timeframe

From the first dose through 30 days after the last dose of study medication (Up to 15 months)

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: Only descriptive statistics were planned for this endpoint.
[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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	9
Units: participants	0	0

No statistical analyses for this end point

Primary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1)

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End point title

Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1) ^[7] ^[8]

End point description

Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate. Data for this endpoint was not summarized for Phase 1 participants only, data was summarized together for Phase 1 and 2 participants in brentuximab 1.4 mg/kg and 1.8 mg/kg arms groups.

End point type

Primary

End point timeframe

Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose

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: Only descriptive statistics were planned for this endpoint.
[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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1
Number of subjects analysed	0 ^[9]
Units: ng/mL
arithmetic mean (standard deviation)	( )

Notes
[9] - Data has been presented in endpoint 19.

No statistical analyses for this end point

Primary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1)

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End point title

Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1) ^[10] ^[11]

End point description

Blood samples were collected and tested for conjugated and unconjugated antibodies. Data for thisendpoint was not summarized for Phase 1 participants only, data was summarized together for Phase 1 and 2 participants in brentuximab 1.4 mg/kg and 1.8 mg/kg arms groups.

End point type

Primary

End point timeframe

Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose

Notes
[10] - 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: Only descriptive statistics were planned for this endpoint.
[11] - 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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1
Number of subjects analysed	0 ^[12]
Units: ug/mL
arithmetic mean (standard deviation)	( )

Notes
[12] - Data has been presented in endpoint 20.

No statistical analyses for this end point

Primary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1)

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End point title

Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1) ^[13] ^[14]

End point description

Blood samples were collected and tested for MMAE plasma concentrations. Data for this endpoint was not summarized for Phase 1 participants only, data was summarized together for Phase 1 and 2 participants in brentuximab 1.4 mg/kg and 1.8 mg/kg arms groups.

End point type

Primary

End point timeframe

Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-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: Only descriptive statistics were planned 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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1
Number of subjects analysed	0 ^[15]
Units: ng/mL
arithmetic mean (standard deviation)	( )

Notes
[15] - Data has been presented in endpoint 21.

No statistical analyses for this end point

Primary: Overall Response Rate (ORR) (Phase 1 and 2)

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End point title

Overall Response Rate (ORR) (Phase 1 and 2) ^[16]

End point description

Overall response rate is defined as the percentage of participants with complete remission (CR) or partial remission (PR) as assessed by an independent review facility (IRF) using International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. Response-evaluable population included participants who received at least 1 dose of study drug, have measurable disease at baseline, and 1 postbaseline disease assessment. Data was summarized together for Phase 1 and 2 participants in brentuximab 1.8 mg/kg arm group.

End point type

Primary

End point timeframe

Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or end of treatment (EOT) (Up to 15 months)

Notes
[16] - 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: Only descriptive statistics were planned for this endpoint.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	15	17
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 71)	47 (21 to 73)	53 (28 to 77)

No statistical analyses for this end point

Secondary: Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)

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End point title

Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)

End point description

Blood samples were collected to assess the immunogenicity of brentuximab vedotin (ATA and nATA development) using a laboratory test. ATA-positive samples were further characterized as transiently ATA positive (defined as 1 or 2 post-Baseline ATA-positive responses), persistently ATA positive (defined as more than 2 post-Baseline ATA positive responses), and nATA positive or negative. Participants from the Safety Population, all enrolled participants who received at least one dose of brentuximab vedotin, with data available for analysis.

End point type

Secondary

End point timeframe

Baseline up to EOT (Up to 15 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: participants
ATA status: Transiently positive	1	4	7
ATA status: Persistently positive	0	2	0
nATA status: Positive	0	5	4

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) (Phase 1)

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End point title

Overall Response Rate (ORR) (Phase 1) ^[17]

End point description

Overall response rate is defined as the percentage of participants with CR or PR as assessed by an IRF using IWG Revised Response Criteria for Malignant Lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. Response-evaluable population included participants who received at least 1 dose of study drug, have measurable disease at baseline, and 1 postbaseline disease assessment. Participants enrolled in Phase 1 of the study were evaluated for this endpoint.

End point type

Secondary

End point timeframe

Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months)

Notes
[17] - 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: This endpoint was planned to be assessed in Phase 1 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	8
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 71)	63 (24 to 91)

No statistical analyses for this end point

Secondary: Time to Progression (TTP) (Phase 1 and 2)

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End point title

Time to Progression (TTP) (Phase 1 and 2)

End point description

TTP is defined as the time in months from first dose until the first subsequent documentation of objective tumor progression. Progressive disease (PD) is defined as any new lesion or increase by ≥50% of previously involved sites from nadir. Safety population is defined as all participants who received at least 1 dose of study drug. TTP was censored on last radiological assessment of measured lesions documenting absence of PD for participants who did not have tumor progression. Safety population is defined as all participants who received at least 1 dose of study drug. TTP was censored on last radiological assessment of measured lesions documenting absence of PD for participants who did not have tumor progression. Here, 9999 indicates upper limit of confidence interval was not reached due to low number of participants with events.

End point type

Secondary

End point timeframe

Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death (Up to 27 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: months
median (confidence interval 95%)	2.7 (1.4 to 2.8)	4.8 (1.2 to 9999)	6.2 (2.8 to 9999)

No statistical analyses for this end point

Secondary: Time to Response (Phase 1 and 2)

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End point title

Time to Response (Phase 1 and 2)

End point description

Time to response is defined as the time in months from the first dose of study treatment until the date of the first assessment of confirmed CR or PR. as assessed by an IRF using IWG revised response criteria for malignant lymphoma. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. Response-evaluable population included participants who received at least 1 dose of study drug, have measurable disease at baseline, and 1 postbaseline disease assessment. Time to response was censored on the last radiological assessment of measured lesions documenting absence of CR or PR for participants who did not have CR or PR. Here, 9999 indicates upper limit of confidence interval was not reached due to low number of participants with events. 99999 indicates median was not reached as no participant had response.

End point type

Secondary

End point timeframe

Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT (Up to 15 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	15	17
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	2.7 (1.3 to 9999)	1.5 (1.2 to 9999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) (Phase 1 and 2)

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End point title

Duration of Response (DOR) (Phase 1 and 2)

End point description

DOR is defined as the time in months from the date of first documentation of a CR or PR to the date of first documentation of tumor progression or PD per IRF assessment according to IWG criteria or to death due to any cause, whichever comes first. CR is defined as the disappearance of all evidence of disease and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. Participants with response from the Safety Population, all enrolled participants who received at least one dose of brentuximab vedotin, with data available for analysis. Duration of response was censored at last observation documenting absence of PD for participants who did not have tumor progression. Here, 99999 indicates median and CI limits were not reached due to low number of participants with events.

End point type

Secondary

End point timeframe

Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death or end of study (Up to 72 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	0 ^[18]	7	9
Units: months
median (confidence interval 95%)	( to )	99999 (2.2 to 99999)	30.3 (3.4 to 30.3)

Notes
[18] - Number of Subjects Analyzed were Zero.

No statistical analyses for this end point

Secondary: Event Free Survival (EFS) (Phase 1 and 2)

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End point title

Event Free Survival (EFS) (Phase 1 and 2)

End point description

EFS is defined as the time in months from first dose until any cause of treatment failure: disease progression, premature discontinuation of treatment for any reason, or death due to any cause, whichever occurs first. PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. Safety population is defined as all participants who received at least 1 dose of study drug. EFS was censored on the last follow-up date if none of the above events occur during the study.

End point type

Secondary

End point timeframe

Cycles 2, 4, 7, 10, 13 and 16 (21-day cycles) until disease progression, death or EOT and then every 12 weeks for 12 months after EOT, until disease progression, or death (Up to 27 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: months
median (confidence interval 95%)	2.7 (1.4 to 2.8)	2.1 (1.2 to 4.8)	4.8 (2.8 to 7.4)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) (Phase 1 and 2)

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End point title

Progression Free Survival (PFS) (Phase 1 and 2)

End point description

PFS is defined as time in months from start of study treatment to first documentation of objective tumor progression per IRF assessment or up to death due to any cause, whichever occurs first. and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir. Safety population is defined as all participants who received at least 1 dose of study drug. PFS was censored on the day following the date of last radiological assessment of measured lesions documenting absence of PD for participants who did not have tumor progression. Here, 9999 indicates upper limit of CI was not reached due to low number of participants with events.

End point type

Secondary

End point timeframe

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: months
median (confidence interval 95%)	2.7 (1.4 to 2.8)	3.8 (1.2 to 9999)	6.2 (2.8 to 31.5)

No statistical analyses for this end point

Secondary: Overall Survival (OS) (Phase 1 and 2)

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End point title

Overall Survival (OS) (Phase 1 and 2)

End point description

OS is the time in months from start of study treatment to date of death due to any cause. Safety population is defined as all participants who received at least 1 dose of study drug. Here, 99999 indicates median was not reached due to low number of participants with events.

End point type

Secondary

End point timeframe

Every 6 months after EOT, until the sooner of death, study closure, or 2 years after enrolment of the last participant (Up to 72 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)

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End point title

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)

End point description

An 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 SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. AE severity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Safety population is defined as all participants who received at least 1 dose of study drug. Data was summarized together for Phase 1 and 2 participants.

End point type

Secondary

End point timeframe

From the first dose through 30 days after the last dose of study medication (up to 15 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: participants
TEAEs	3	16	17
SAEs	0	7	1

No statistical analyses for this end point

Secondary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)

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End point title

Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)

End point description

Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population is defined as all participants who received at least 1 dose of study drug. Data was summarized together for Phase 1 and 2 participants in brentuximab 1.8 mg/kg arm group.

End point type

Secondary

End point timeframe

From the first dose through 30 days after the last dose of study medication (Up to 15 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: participants
Gamma-glutamyltransferase increased	0	2	0
Alanine aminotransferase increased	0	1	0
Aspartate aminotransferase increased	0	1	0
Transaminases increased	0	1	0
Lymphocyte count decreased	1	0	2
Neutrophil count decreased	0	0	2
White blood cell count decreased	0	0	1
Blood bicarbonate decreased	0	1	0
Weight decreased	0	0	1
C-reactive protein increased	0	1	0
Blood alkaline phosphatase increased	0	1	0

No statistical analyses for this end point

Secondary: Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)

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End point title

Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)

End point description

End point type

Secondary

End point timeframe

From the first dose through 30 days after the last dose of study medication (Up to 15 months)

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Number of subjects analysed	3	16	17
Units: participants	0	0	0

No statistical analyses for this end point

Secondary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2)

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End point title

Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2) ^[19]

End point description

Blood samples were collected and tested for serum concentrations of brentuximab vedotin antibody-drug conjugate. PK-evaluable population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Cycle 2 Day 2 values are collected in phase 1 participants only. Data was summarized together for all participants in brentuximab vedotin 1.8 mg/kg arm group. Here, 999999 indicates arithmetic mean and standard deviation was not estimable since the number of participants analyzed were '0'. n is the number of participants analyzed at the given time-point.

End point type

Secondary

End point timeframe

Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-dose

Notes
[19] - 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: The data for this endpoint was planned to be assessed in combined form for Phase 2 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	33 ^[20]
Units: ug/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1, Pre-Dose (n=0,33)	999999 ( 999999 )	99999 ( 99999 )
Cycle 1 Day 1, 5 Minutes Post-Dose (n=3,33)	23.1 ( 3.46 )	31.8 ( 12.4 )
Cycle 1 Day 2, 24 Hours Post-Dose (n=3,32)	9.50 ( 1.73 )	13.0 ( 5.34 )
Cycle 1 Day 3, 48 Hours Post-Dose (n=3,31)	5.67 ( 0.924 )	12.0 ( 16.3 )
Cycle 1 Day 5, 96 Hours Post-Dose (n=3,31)	3.50 ( 1.41 )	8.68 ( 13.4 )
Cycle 1 Day 14, 312 Hours Post-Dose (n=3,31)	0.844 ( 0.309 )	2.19 ( 3.44 )
Cycle 2 Day 1, Pre-Dose (n=3,32)	0.149 ( 0.128 )	0.395 ( 0.322 )
Cycle 2 Day 1, 5-minutes Post-Dose (n=3,30)	25.3 ( 7.56 )	32.9 ( 9.80 )
Cycle 2 Day 2, 24 Hours Post-Dose (n=3,10)	8.80 ( 6.19 )	10.4 ( 8.05 )
Cycle 2 Day 3, 48 Hours Post-Dose (n=3,29)	3.70 ( 1.95 )	11.4 ( 16.8 )
Cycle 2 Day 5, 96 Hours Post-Dose (n=3,27)	2.04 ( 1.26 )	9.61 ( 17.9 )
Cycle 3 Day 1, Pre-Dose (n=2,26)	0.116 ( 0.163 )	0.491 ( 0.387 )
Cycle 3 Day 1, 5 minutes Post-Dose (n=2,26)	23.9 ( 2.83 )	31.3 ( 9.79 )
Cycle 4 Day 1, Pre-dose (n=2,21)	0.218 ( 0.271 )	0.691 ( 0.492 )
Cycle 4 Day 1, 5 minutes Post-Dose (n=2,21)	22.9 ( 4.60 )	30.0 ( 12.2 )
Cycle 5 Day 1, Pre-Dose (n=2,21)	0.264 ( 0.321 )	0.845 ( 0.564 )
Cycle 5 Day 1, 5 minutes Post-Dose (n=2,21)	22.5 ( 3.32 )	30.6 ( 15.1 )
Cycle 6 Day 1, Pre-Dose (n=2,17)	0.312 ( 0.351 )	1.06 ( 0.699 )
Cycle 6 Day 1, 5 minutes Post-Dose (n=2,17)	20.3 ( 4.38 )	33.2 ( 16.1 )
Cycle 7 Day 1, Pre-Dose (n=2,17)	0.327 ( 0.337 )	1.04 ( 0.618 )
Cycle 7 Day 1, 5 minutes Post-Dose (n=2,17)	17.9 ( 2.40 )	32.3 ( 15.4 )
Cycle 8 Day 1, Pre-Dose (n=0,14)	999999 ( 999999 )	1.25 ( 0.565 )
Cycle 8 Day 1, 5 minutes Post-Dose (n=0,13)	999999 ( 999999 )	35.2 ( 10.5 )
Cycle 8 Day 2, 24 Hours Post-Dose (n=0,13)	999999 ( 999999 )	14.0 ( 4.55 )
Cycle 8 Day 3, 48 Hours Post-Dose (n=0,13)	999999 ( 999999 )	9.53 ( 2.96 )
Cycle 8 Day 5, 96 Hours Post-Dose (n=0,12)	999999 ( 999999 )	6.44 ( 2.35 )
Cycle 8 Day 14, 312 Hours Post-Dose (n=0,13)	999999 ( 999999 )	3.30 ( 4.63 )
Cycle 9 Day 1, Pre-Dose (n=0,14)	999999 ( 999999 )	4.37 ( 11.7 )
Cycle 9 Day 1, 5 Minutes Post-Dose (n=0,13)	999999 ( 999999 )	29.6 ( 11.3 )
Cycle 10 Day 1, Pre-Dose (n=0,11)	999999 ( 999999 )	1.20 ( 0.455 )
Cycle 10 Day 1, 5 minutes Post-Dose (n=0,12)	999999 ( 999999 )	35.7 ( 9.50 )
Cycle 11 Day 1, Pre-Dose (n=0,8)	999999 ( 999999 )	1.84 ( 1.57 )
Cycle 11 Day 1, 5 minutes Post-Dose (n=0,8)	999999 ( 999999 )	35.7 ( 10.8 )
Cycle 12 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	1.47 ( 0.665 )
Cycle 12 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	40.0 ( 10.4 )
Cycle 13 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	6.28 ( 11.5 )
Cycle 13 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	33.3 ( 16.1 )
Cycle 14 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	1.60 ( 0.600 )
Cycle 14 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	37.0 ( 7.92 )
Cycle 15 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	1.48 ( 0.542 )
Cycle 15 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	40.3 ( 10.6 )
Cycle 16 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	1.52 ( 0.361 )
Cycle 16 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	41.5 ( 4.70 )

Notes
[20] - Here, 99999 indicates data was below the limit of quantification.

No statistical analyses for this end point

Secondary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

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End point title

Serum Concentration of Total Antibodies (Conjugated and Unconjugated) ^[21]

End point description

Blood samples were collected and tested for conjugated and unconjugated antibodies. PK-evaluable population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Cycle 2 Day 2 values are collected in phase 1 participants only. Data was summarized together for all participants in brentuximab vedotin 1.8 mg/kg arm group. Here, 999999 indicates arithmetic mean and standard deviation was not estimable since the number of participants analyzed were '0'. 99999 indicates data was below the limit of quantification. n is the number of participants analyzed at the given time-point.

End point type

Secondary

End point timeframe

Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-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: The data for this endpoint was planned to be assessed in combined form for Phase 2 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	33 ^[22]
Units: ug/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1, Pre-Dose (n=2,32)	99999 ( 99999 )	99999 ( 99999 )
Cycle 1 Day 1, 5 Minutes Post-Dose (n=3,33)	26.3 ( 2.29 )	34.7 ( 13.4 )
Cycle 1 Day 2, 24 Hours Post-Dose (n=3,33)	16.7 ( 1.50 )	25.0 ( 9.59 )
Cycle 1 Day 3, 48 Hours Post-Dose (n=3,33)	12.7 ( 3.13 )	18.5 ( 7.57 )
Cycle 1 Day 5, 96 Hours Post-Dose (n=3,33)	8.63 ( 5.11 )	11.8 ( 5.02 )
Cycle 1 Day 14, 312 Hours Post-Dose (n=3,32)	2.23 ( 0.833 )	3.50 ( 1.70 )
Cycle 2 Day 1, Pre-Dose (n=3,32)	0.470 ( 0.459 )	1.16 ( 0.825 )
Cycle 2 Day 1, 5-minutes Post-Dose (n=3,31)	26.9 ( 7.98 )	35.6 ( 12.0 )
Cycle 2 Day 2, 24 Hours Post-Dose (n=3,10)	17.1 ( 10.4 )	17.2 ( 7.93 )
Cycle 2 Day 3, 48 Hours Post-Dose (n=3,31)	9.60 ( 5.39 )	16.0 ( 6.73 )
Cycle 2 Day 3, 96 Hours Post-Dose (n=3,30)	6.43 ( 3.69 )	10.2 ( 5.16 )
Cycle 3 Day 1, Pre-Dose (n=2,26)	0.415 ( 0.586 )	1.62 ( 1.07 )
Cycle 3 Day 1, 5 minutes Post-Dose (n=2,26)	30.0 ( 5.87 )	38.2 ( 13.1 )
Cycle 4 Day 1, Pre-dose (n=2,21)	0.875 ( 1.03 )	1.95 ( 1.26 )
Cycle 4 Day 1, 5 minutes Post-Dose (n=2,21)	29.6 ( 8.13 )	37.1 ( 15.6 )
Cycle 5 Day 1, Pre-Dose (n=2,21)	0.844 ( 0.928 )	2.45 ( 1.68 )
Cycle 5 Day 1, 5 minutes Post-Dose (n=2,21)	29.4 ( 3.04 )	38.0 ( 18.8 )
Cycle 6 Day 1, Pre-Dose (n=2,17)	1.05 ( 1.20 )	2.99 ( 1.81 )
Cycle 6 Day 1, 5 minutes Post-Dose (n=2,17)	29.4 ( 5.37 )	39.8 ( 19.8 )
Cycle 7 Day 1, Pre-Dose (n=2,17)	0.995 ( 0.998 )	2.92 ( 1.62 )
Cycle 7 Day 1, 5 minutes Post-Dose (n=2,17)	24.0 ( 2.69 )	41.0 ( 21.2 )
Cycle 8 Day 1, Pre-Dose (n=0,14)	999999 ( 999999 )	3.29 ( 1.14 )
Cycle 8 Day 1, 5 minutes Post-Dose (n=0,14)	999999 ( 999999 )	41.4 ( 9.47 )
Cycle 8 Day 2, 24 Hours Post-Dose (n=0,14)	999999 ( 999999 )	28.2 ( 6.38 )
Cycle 8 Day 3, 48 Hours Post-Dose (n=0,14)	999999 ( 999999 )	22.9 ( 5.67 )
Cycle 8 Day 5, 96 Hours Post-Dose (n=0,14)	999999 ( 999999 )	17.3 ( 4.93 )
Cycle 8 Day 14, 312 Hours Post-Dose (n=0,13)	999999 ( 999999 )	5.74 ( 2.02 )
Cycle 9 Day 1, Pre-Dose (n=0,14)	999999 ( 999999 )	6.30 ( 12.0 )
Cycle 9 Day 1, 5 Minutes Post-Dose (n=0,13)	999999 ( 999999 )	35.1 ( 11.3 )
Cycle 10 Day 1, Pre-Dose (n=0,12)	999999 ( 999999 )	3.48 ( 1.13 )
Cycle 10 Day 1, 5 minutes Post-Dose (n=0,12)	999999 ( 999999 )	41.4 ( 8.63 )
Cycle 11 Day 1, Pre-Dose (n=0,8)	999999 ( 999999 )	3.96 ( 2.24 )
Cycle 11 Day 1, 5 minutes Post-Dose (n=0,8)	999999 ( 999999 )	42.8 ( 8.85 )
Cycle 12 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	3.47 ( 1.28 )
Cycle 12 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	44.8 ( 10.3 )
Cycle 13 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	11.3 ( 17.1 )
Cycle 13 Day 1, 5 minutes Post-Dose (n=3,32)	999999 ( 999999 )	40.3 ( 19.2 )
Cycle 14 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	3.97 ( 1.14 )
Cycle 14 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	44.5 ( 7.05 )
Cycle 15 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	4.02 ( 1.40 )
Cycle 15 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	49.7 ( 6.88 )
Cycle 16 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	4.60 ( 1.67 )
Cycle 16 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	49.7 ( 7.61 )

Notes
[22] - Here, 99999 indicates data was below the limit of quantification.

No statistical analyses for this end point

Secondary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2)

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End point title

Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2) ^[23]

End point description

Blood samples were collected and tested for MMAE plasma concentrations. PK-evaluable population was defined as participants with sufficient dosing and PK data to reliably estimate PK parameters. Cycle 2 Day 2 values are collected in phase 1 participants only. Data was summarized together for all participants in brentuximab vedotin 1.8 mg/kg arm group. Here, 999999 indicates arithmetic mean and standard deviation was not estimable since the number of participants analyzed were '0'. 99999 indicates data was below the limit of quantification. n is the number of participants analyzed at the given time-point.

End point type

Secondary

End point timeframe

Cycle 1 and 8 pre-dose and 5 minutes, 24, 48, 96 and 312 hours post-dose; Cycle 2 pre-dose, 5 minutes and 24, 48 and 96 hours post-dose; Cycle 3 to 16 pre-dose and 5 minutes post-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: The data for this endpoint was planned to be assessed in combined form for Phase 2 arm groups.

End point values	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1
Number of subjects analysed	3	33 ^[24]
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1, Pre-Dose (n=2,32)	99999 ( 99999 )	99999 ( 99999 )
Cycle 1 Day 1, 5 Minutes Post-Dose (n=3,32)	0.416 ( 0.480 )	0.368 ( 0.309 )
Cycle 1 Day 2, 24 Hours Post-Dose (n=3,32)	4.63 ( 3.20 )	4.88 ( 3.55 )
Cycle 1 Day 3, 48 Hours Post-Dose (n=3,32)	4.20 ( 1.95 )	5.36 ( 3.72 )
Cycle 1 Day 5, 96 Hours Post-Dose (n=3,32)	2.80 ( 0.300 )	4.43 ( 3.04 )
Cycle 1 Day 14, 312 Hours Post-Dose (n=3,31)	0.196 ( 0.0641 )	0.530 ( 0.552 )
Cycle 2 Day 1, Pre-Dose (n=3,29)	0.0647 ( 0.0358 )	0.0739 ( 0.0640 )
Cycle 2 Day 1, 5-minutes Post-Dose (n=3,29)	0.556 ( 0.562 )	0.478 ( 0.461 )
Cycle 2 Day 2, 24 Hours Post-Dose (n=3,8)	5.63 ( 5.72 )	3.71 ( 3.94 )
Cycle 2 Day 3, 48 Hours Post-Dose (n=3,30)	4.60 ( 3.70 )	3.86 ( 3.18 )
Cycle 2 Day 5, 96 Hours Post-Dose (n=3,29)	2.60 ( 1.04 )	2.70 ( 1.69 )
Cycle 3 Day 1, Pre-Dose (n=2,26)	0.0250 ( 0.0354 )	0.0650 ( 0.0590 )
Cycle 3 Day 1, 5 minutes Post-Dose (n=2,25)	0.216 ( 0.0361 )	0.514 ( 0.684 )
Cycle 4 Day 1, Pre-dose (n=2,19)	0.0565 ( 0.00495 )	0.0866 ( 0.0784 )
Cycle 4 Day 1, 5 minutes Post-Dose (n=2,19)	0.234 ( 0.0742 )	0.376 ( 0.449 )
Cycle 5 Day 1, Pre-Dose (n=2,18)	0.0820 ( 9999 )	0.0862 ( 0.0729 )
Cycle 5 Day 1, 5 minutes Post-Dose (n=2,18)	0.334 ( 0.0955 )	0.301 ( 0.248 )
Cycle 6 Day 1, Pre-Dose (n=2,15)	0.0680 ( 0.0156 )	0.0841 ( 0.0632 )
Cycle 6 Day 1, 5 minutes Post-Dose (n=2,15)	0.247 ( 0.00707 )	0.450 ( 0.663 )
Cycle 7 Day 1, Pre-Dose (n=2,16)	0.104 ( 0.0389 )	0.0830 ( 0.0578 )
Cycle 7 Day 1, 5 minutes Post-Dose (n=2,15)	0.326 ( 0.0361 )	0.310 ( 0.282 )
Cycle 8 Day 1, Pre-Dose (n=0,13)	999999 ( 999999 )	0.101 ( 0.934 )
Cycle 8 Day 1, 5 minutes Post-Dose (n=0,12)	999999 ( 999999 )	0.295 ( 0.151 )
Cycle 8 Day 2, 24 Hours Post-Dose (n=0,13)	999999 ( 999999 )	1.96 ( 1.31 )
Cycle 8 Day 3, 48 Hours Post-Dose\|	999999 ( 999999 )	1.91 ( 1.29 )
Cycle 8 Day 5, 96 Hours Post-Dose (n=0,13)	999999 ( 999999 )	2.00 ( 1.05 )
Cycle 8 Day 14, 312 Hours Post-Dose (n=0,12)	999999 ( 999999 )	0.325 ( 0.214 )
Cycle 9 Day 1, Pre-Dose (n=0,13)	999999 ( 999999 )	0.0819 ( 0.0496 )
Cycle 9 Day 1, 5 Minutes Post-Dose (n=0,12)	999999 ( 999999 )	0.218 ( 0.128 )
Cycle 10 Day 1, Pre-Dose (n=0,12)	999999 ( 999999 )	0.727 ( 0.0517 )
Cycle 10 Day 1, 5 minutes Post-Dose (n=0,12)	999999 ( 999999 )	0.204 ( 0.0982 )
Cycle 11 Day 1, Pre-Dose (n=0,7)	999999 ( 999999 )	0.0763 ( 0.0368 )
Cycle 11 Day 1, 5 minutes Post-Dose (n=0,7)	999999 ( 999999 )	0.255 ( 0.133 )
Cycle 12 Day 1, Pre-Dose (n=0,5)	999999 ( 999999 )	0.105 ( 0.0983 )
Cycle 12 Day 1, 5 minutes Post-Dose (n=0,5)	999999 ( 999999 )	0.252 ( 0.116 )
Cycle 13 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	0.110 ( 0.0629 )
Cycle 13 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	0.244 ( 0.130 )
Cycle 14 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	0.109 ( 0.0529 )
Cycle 14 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	0.320 ( 0.138 )
Cycle 15 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	0.0843 ( 0.0548 )
Cycle 15 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	0.404 ( 0.192 )
Cycle 16 Day 1, Pre-Dose (n=0,6)	999999 ( 999999 )	0.139 ( 0.0926 )
Cycle 16 Day 1, 5 minutes Post-Dose (n=0,6)	999999 ( 999999 )	0.381 ( 0.277 )

Notes
[24] - Here, 99999 indicates data was below the limit of quantification.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose through 30 days after the last dose of study medication (Up to 15 months)

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Brentuximab vedotin 1.4 mg/kg: Phase 1

Reporting group description

Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

Reporting group title

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only

Reporting group description

Reporting group title

Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only

Reporting group description

Serious adverse events	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 3 (0.00%)	7 / 16 (43.75%)	1 / 17 (5.88%)
number of deaths (all causes)	1	6	2
number of deaths resulting from adverse events	0	0	0
Cardiac disorders
Supraventricular tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
Additional description: One treatment-emergent death occurred during treatment with brentuximab 1.8 mg/kg and was not related.
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Brentuximab vedotin 1.4 mg/kg: Phase 1	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r HL only	Brentuximab vedotin 1.8 mg/kg: Phase 1 and 2 r/r sALCL only
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	16 / 16 (100.00%)	17 / 17 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 16 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	8 / 16 (50.00%)	7 / 17 (41.18%)
occurrences all number	1	11	10
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	1 / 17 (5.88%)
occurrences all number	0	2	1
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	3
Feeling hot
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	3 / 16 (18.75%)	1 / 17 (5.88%)
occurrences all number	0	4	2
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	3	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	3	0
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Lymphocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 16 (0.00%)	2 / 17 (11.76%)
occurrences all number	1	0	3
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	2
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
C-reactive protein increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Injury, poisoning and procedural complications
Joint dislocation
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Muscle strain
subjects affected / exposed	1 / 3 (33.33%)	0 / 16 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Head injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Facial bones fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Paraesthesia
subjects affected / exposed	1 / 3 (33.33%)	5 / 16 (31.25%)	1 / 17 (5.88%)
occurrences all number	2	5	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	2 / 17 (11.76%)
occurrences all number	0	2	8
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Peripheral motor neuropathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	3 / 17 (17.65%)
occurrences all number	0	0	3
Migraine
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Dysgeusia
subjects affected / exposed	1 / 3 (33.33%)	0 / 16 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Vocal cord paralysis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	4 / 16 (25.00%)	1 / 17 (5.88%)
occurrences all number	0	6	3
Lymph node pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	1 / 17 (5.88%)
occurrences all number	0	2	1
Lymphadenopathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	6	0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Eye disorders
Eye discharge
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 3 (66.67%)	7 / 16 (43.75%)	4 / 17 (23.53%)
occurrences all number	2	9	5
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	3 / 17 (17.65%)
occurrences all number	0	3	3
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	2 / 16 (12.50%)	1 / 17 (5.88%)
occurrences all number	1	2	2
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	1	2	0
Gastrointestinal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	3 / 17 (17.65%)
occurrences all number	0	3	3
Constipation
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Toothache
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Gastrointestinal motility disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Odynophagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Hypertransaminasaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hepatic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	2
Blister
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Dermatosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	2
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Seborrhoeic dermatitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Drug eruption
subjects affected / exposed	1 / 3 (33.33%)	0 / 16 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Erythema multiforme
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Urinary tract pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	1 / 17 (5.88%)
occurrences all number	0	2	1
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	4 / 16 (25.00%)	0 / 17 (0.00%)
occurrences all number	0	5	0
Arthralgia
subjects affected / exposed	1 / 3 (33.33%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	1	1	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Infections and infestations
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	3 / 16 (18.75%)	4 / 17 (23.53%)
occurrences all number	0	3	5
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	3 / 16 (18.75%)	3 / 17 (17.65%)
occurrences all number	0	4	4
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Upper respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 16 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Tooth abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Clostridium difficile colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	3 / 16 (18.75%)	0 / 17 (0.00%)
occurrences all number	0	3	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 16 (12.50%)	1 / 17 (5.88%)
occurrences all number	0	3	1
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 16 (6.25%)	0 / 17 (0.00%)
occurrences all number	0	1	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 16 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

11 Jul 2011

The amendment promoted participant safety by reducing the opportunity for potential drug-drug interactions, using an objective definition of dose-limiting toxicity (DLT), and specifying administration equipment that ensures drug compatibility.

06 Feb 2012

• The protocol excluded participants with signs or symptoms of progressive multifocal leukoencephalopathy (PML) and instructed for management of suspected PML as brentuximab vedotin discontinuation. • Information was added on management of infusion-related reactions, including instructions to immediately and permanently discontinue administration of brentuximab vedotin for Grade 3 or higher infusion-related reactions consistent with anaphylaxis. • Included information on occurrence of pulmonary toxicity and specifies that concomitant use of bleomycin with brentuximab vedotin is contraindicated. • The original protocol stated that brentuximab vedotin dose should be held in case of new or worsening events of Grade 2 or 3 neuropathy. To ensure participant’s safety and conform to dosing guidelines, an exclusion criterion was added for participants with Grade 2/higher peripheral neuropathy at the time of screening. • Participants who were pregnant or both lactating and breastfeeding were not eligible for the study. This exclusion criterion was inadvertently omitted from original protocol and was added to this amendment. • A washout period of at least 14 days was required for participants who received local palliative radiation therapy; a washout period of at least 84 days was required for participants who received radiation therapy to more than 25% of bone marrow-containing spaces. Exclusion criteria was added to specify the restrictions on receiving radiation therapy prior to first dose of study drug. • Planned imaging assessments were revised in order to minimize radiation exposure in this pediatric population. Magnetic resonance imaging (MRI) was to be performed for neck, abdomen, and pelvis evaluations; computed tomography (CT) scans were to be used for chest evaluations only. • The definition of enrollment was changed to at the time of first dose of study drug. • The contact information for serious adverse events (SAEs) and events of pregnancy was revised.

12 Jun 2014

• Duration of follow-up was changed to align with content of pediatric investigation plan. PIP states that participants will be followed for safety and survival for 2 years after enrollment. References to follow-up revised to state that participants will be followed for progression-free survival and overall survival every 12 weeks for 12 months after End of Treatment visit. Thereafter, assessment for OS was to continue every 6 months until sooner of death or study closure or a maximum of 2 years after enrollment of last participant. • Described study procedures for participants who continue to receive brentuximab vedotin after Cycle 16 and further clarifies other study procedures associated with study conduct. • Clarified primary endpoint for phase 2 of study is best overall response rate Inclusion criterion for total bilirubin has been revised to include participants with total serum bilirubin ≤ 3 times upper limit of normal range (ULN) if abnormal value is due to indirect hyperbilirubinemia due to Gilbert’s disease. • Participants with elevated alanine aminotransferase or aspartate aminotransferase values 5 times ULN may be enrolled if elevation can be reasonably ascribed to presence of metastatic disease in liver. • Exclusions of previous allogeneic stem cell transplant or autologous stem cell infusion was changed from within 6 months and 6 weeks before first dose of study drug, respectively, to within 3 months and 4 weeks before first dose of study drug, respectively. • Exclusion criterion for cytochrome P450 3A4 inhibitors was changed to exclude both strong and listed moderate inhibitors of CYP3A4 within 2 weeks before first dose of study drug, and a change to timing for exclusion of corticosteroids. • Following potential risks were added to Risks in Children section to align with updates to safety profile of brentuximab vedotin: Stevens-Johnson syndrome, pancreatitis, hepatotoxicity (elevated AST and ALT).

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: A Phase 1/2 Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1)

Primary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1)

Primary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1)

Primary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1)

Primary: Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1)

Primary: Number of Participants with Clinically Significant Vital Signs Values Reported as AEs (Phase 1)

Primary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1)

Primary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1)

Primary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1)

Primary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated) (Phase 1)

Primary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1)

Primary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1)

Primary: Overall Response Rate (ORR) (Phase 1 and 2)

Primary: Overall Response Rate (ORR) (Phase 1 and 2)

Secondary: Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)

Secondary: Number of Participants with Antitherapeutic Antibodies (ATA) and Neutralizing ATA (nATA) (Phase 1 and 2)

Secondary: Overall Response Rate (ORR) (Phase 1)

Secondary: Overall Response Rate (ORR) (Phase 1)

Secondary: Time to Progression (TTP) (Phase 1 and 2)

Secondary: Time to Progression (TTP) (Phase 1 and 2)

Secondary: Time to Response (Phase 1 and 2)

Secondary: Time to Response (Phase 1 and 2)

Secondary: Duration of Response (DOR) (Phase 1 and 2)

Secondary: Duration of Response (DOR) (Phase 1 and 2)

Secondary: Event Free Survival (EFS) (Phase 1 and 2)

Secondary: Event Free Survival (EFS) (Phase 1 and 2)

Secondary: Progression Free Survival (PFS) (Phase 1 and 2)

Secondary: Progression Free Survival (PFS) (Phase 1 and 2)

Secondary: Overall Survival (OS) (Phase 1 and 2)

Secondary: Overall Survival (OS) (Phase 1 and 2)

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)

Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1 and 2)

Secondary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)

Secondary: Number of Participants with Abnormal Clinical Laboratory Values Reported as AEs (Phase 1 and 2)

Secondary: Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)

Secondary: Number of Participants with Clinically Significant Vital Signs Reported as AEs (Phase 1 and 2)

Secondary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2)

Secondary: Antibody-drug Conjugate (ADC) Serum Concentrations (Phase 1 and 2)

Secondary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

Secondary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

Secondary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2)

Secondary: Monomethyl Auristatin E (MMAE) Plasma Concentrations (Phase 1 and 2)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1/2 Study of Brentuximab Vedotin (SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma.