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Clinical Trial Results:
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of a Novel Transforming Growth Factor-beta Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors (Phase 1b) and in Recurrent or Refractory Non-small Cell Lung Cancer, Hepatocellular Carcinoma, or Glioblastoma (Phase 2)

Summary
EudraCT number	2015-002093-20
Trial protocol	DE
Global end of trial date	08 Jul 2020

Results information
Results version number	v2(current)
This version publication date	03 Nov 2021
First version publication date	18 Jul 2021
Other versions	v1
Version creation reason	Correction of full data set Separate cohorts for Phase 2 PK data.

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

H9H-MC-JBEF

ISRCTN number

US NCT number

NCT02423343

WHO universal trial number (UTN)

Other trial identifiers

Trial Number: 15702

Sponsor organisation name

Eli Lilly and Company

Sponsor organisation address

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Public contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Scientific contact

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,

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

08 Jul 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jul 2020

Was the trial ended prematurely?

Main objective of the trial

The main purpose of this study is to evaluate the safety, tolerability, and efficacy of the study drug known as galunisertib in combination with nivolumab in participants with advanced refractory solid tumors and in recurrent or refractory non-small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC).

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Jan 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 13

Country: Number of subjects enrolled

Spain: 28

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

Due low enrollment, the Hepatocellular Carcinoma (HCC) cohort was terminated early.

Screening details

Participants who had at least one post baseline tumor assessment were considered to have completed the study.

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

Galunisertib + Nivolumab (Cohort 1) Phase 1b

Arm description

50 milligram (mg) Galunisertib administered orally daily (QD) on Day 1 through Day 14 of each 4-week cycle in combination with 3 milligrams per kilogram (3 mg/kg) nivolumab given intravenously (IV), every 2 weeks (Q2W), on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

OPDIVO®

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Administered IV

Galunisertib + Nivolumab (Cohort 2) Phase 1b

Arm description

50 mg Galunisertib administered orally twice daily (BID) on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Administered IV

Galunisertib + Nivolumab (Cohort 3) Phase 1b

Arm description

80 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Administered IV

Galunisertib + Nivolumab (Cohort 4) Phase 1b

Arm description

150 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Administered IV

Galunisertib + Nivolumab (NSCLC) Phase 2

Arm description

150 mg Galunisertib administered orally BID for the first 14 days of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met.

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Administered IV

Galunisertib + Nivolumab (HCC) Phase 2

Arm description

Arm type

Experimental

Investigational medicinal product name

Galunisertib

Investigational medicinal product code

Other name

LY2157299

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Administered IV

Number of subjects in period 1	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Started	3	5	3	4	25	1
Received at Least 1 Dose of Study Drug	3	5	3	4	25	1
Completed	3	4	3	4	20	1
Not completed	0	1	0	0	5	0
Adverse event, serious fatal	-	-	-	-	1	-
Consent withdrawn by subject	-	1	-	-	-	-
Adverse event, non-fatal	-	-	-	-	2	-
Progressive Disease	-	-	-	-	2	-

Baseline characteristics

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Reporting group title

Galunisertib + Nivolumab (Cohort 1) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (Cohort 2) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (Cohort 3) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (Cohort 4) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (NSCLC) Phase 2

Reporting group description

Reporting group title

Galunisertib + Nivolumab (HCC) Phase 2

Reporting group description

Reporting group values	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2	Total
Number of subjects	3	5	3	4	25	1	41
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.7 ± 15.6	47.2 ± 15.8	36.0 ± 5.3	61.5 ± 9.0	61.0 ± 8.4	64.0 ± 0.0	-
Gender categorical
Units: Subjects
Female	1	1	1	3	9	1	16
Male	2	4	2	1	16	0	25
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	1	0	0	1	0	0	2
White	2	5	3	3	25	1	39
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0
Region of Enrollment
Units: Subjects
United States	3	3	2	4	1	0	13
Spain	0	2	1	0	24	1	28

End points

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Reporting group title

Galunisertib + Nivolumab (Cohort 1) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (Cohort 2) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (Cohort 3) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (Cohort 4) Phase 1b

Reporting group description

Reporting group title

Galunisertib + Nivolumab (NSCLC) Phase 2

Reporting group description

Reporting group title

Galunisertib + Nivolumab (HCC) Phase 2

Reporting group description

Subject analysis set title

Galunisertib + Nivolumab (NSCLC) Phase 2

Subject analysis set type

Per protocol

Subject analysis set description

150 mg Galunisertib given orally twice daily for the first 14 days of each 4 week cycle in combination with 3 mg/kg nivolumab given IV every 2 weeks (Day 1 and Day 15) of each 4 week cycle. Participants may continue to receive study drug until discontinuation criteria are met.

Subject analysis set title

Phase 1b Participants

Subject analysis set type

Per protocol

Subject analysis set description

Cohort 1: 50 mg Galunisertib administered QD on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, every Q2W, on Day 1 and Day 15 for 2 cycles. Cohort 2: 50 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W on Day 1 and Day 15 for 2 cycles. Cohort 3: 80 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W on Day 1 and Day 15 for 2 cycles. Cohort 4: 150 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W on Day 1 and Day 15 for 2 cycles.

Subject analysis set title

Galunisertib + Nivolumab (NSCLC + HCC) Phase 2

Subject analysis set type

Per protocol

Subject analysis set description

150 mg Galunisertib administered orally BID for the first 14 days of each 4 week cycle in combination with 3 mg/kg nivolumab given IV Q2W (Day 1 and Day 15) of each 4 week cycle. Participants may continue to receive study drug until discontinuation criteria are met.

Subject analysis set title

Galunisertib + Nivolumab (NSCLC) Phase 2

Subject analysis set type

Per protocol

Subject analysis set description

150 mg Galunisertib administered orally BID for the first 14 days of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met.

Subject analysis set title

Galunisertib + Nivolumab (HCC) Phase 2

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Galunisertib + Nivolumab (NSCLC) Phase 2

Subject analysis set type

Per protocol

Subject analysis set description

150 mg Galunisertib administered orally BID for the first 14 days of each 4 week cycle in combination with 3 mg/kg nivolumab given IV Q2W (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met.

Subject analysis set title

Galunisertib + Nivolumab (HCC) Phase 2

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Phase 1b: Maximum Tolerated Dose (MTD) of Galunisertib in Combination with Nivolumab

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End point title

Phase 1b: Maximum Tolerated Dose (MTD) of Galunisertib in Combination with Nivolumab ^[1]

End point description

The MTD is defined as the highest tested dose that has less than 33% probability of causing a dose limiting toxicity (DLT). Analysis Population Description (APD): All participants who received at least one dose of study drug in Phase 1b per protocol.

End point type

Primary

End point timeframe

Cycle 1 through Cycle 2 (Up to 2 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: Per protocol, Maximum Tolerated Dose was assessed during Phase 1b only with all Phase 1b cohorts combined.

End point values	Phase 1b Participants
Number of subjects analysed	15
Units: milligrams (mg)
number (not applicable)	300

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab

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End point title

Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab

End point description

Minimum Concentration (Cmin) of Nivolumab. APD: All participants who received at least one dose of study drug and had evaluable PK data.

End point type

Secondary

End point timeframe

PK: Cycle 1 Day 15 Predose; Cycle 2: Day 1: Pre-dose; Day 15: Predose: Cycle 4: Day 1: Predose

End point values	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	2	5	3	4	11	0 ^[2]
Units: micrograms per milliliter (µg/mL)
arithmetic mean (full range (min-max))	33.5 (19.9 to 53.6)	36.2 (11.8 to 58.1)	43.2 (5.45 to 76)	29.2 (9.39 to 63.7)	37.6 (1.08 to 105)	( to )

Notes
[2] - Cmin PK data was not available for the HCC cohort.

No statistical analyses for this end point

Secondary: PK: Area Under the Plasma Concentration -Time Curve of Galunisertib From Time Zero to 24 Hours (AUC [0-24h]) at Steady State

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End point title

PK: Area Under the Plasma Concentration -Time Curve of Galunisertib From Time Zero to 24 Hours (AUC [0-24h]) at Steady State

End point description

Area under the plasma concentration curve from time zero to 24 hours of galunisertib for Cycle 1 and Cycle 2. APD: All participants who received at least one dose of study drug and had evaluable PK data.

End point type

Secondary

End point timeframe

PK: Cycle 1 and Cycle 2 Day 1: Predose, 0.5 - 3 hours postdose, Cycle 1 and Cycle 2 Day 14: Predose, 0.5 - 2, 3.5 - 5, and 24 hours postdose through Cycle 4 Day 1 predose

End point values	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	3	4	3	4	12	1 ^[3]
Units: microgramshour per liter (μgh/L)
geometric mean (geometric coefficient of variation)	3060 ± 41	2350 ± 46	2220 ± 164	5580 ± 61	7322 ± 67	0 ± 0

Notes
[3] - Geometric Mean (CV) could not be calculated for N=1, individual data reported: 6005: μg*h/L.

No statistical analyses for this end point

Secondary: Number of Participants with Anti-Nivolumab Antibodies When Administered in Combination with Galunisertib

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End point title

Number of Participants with Anti-Nivolumab Antibodies When Administered in Combination with Galunisertib

End point description

Participants with treatment-emergent anti-nivolumab antibodies when administered with galunisertib were participants with a 4-fold or greater increase in titer from baseline measurement (treatment-boosted). If baseline result is ADA not present, then the subject is TE ADA+, if there is at least 1 postbaseline result of ADA present with titer ≥ 40 (treatment-induced). APD: All participants who received at least one dose of study drug and were evaluable for TE ADA.

End point type

Secondary

End point timeframe

Cycle 1: Days 1, 14, 15 Predose and Day 100 Follow-up; Cycles 2 and 4: Day 1 Predose and Day 100 Follow-up

End point values	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	3	5	2	3	13	1
Units: Count of Participants	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Phase 2: Progression Free Survival (PFS)

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End point title

Phase 2: Progression Free Survival (PFS) ^[4]

End point description

PFS was defined as the time from the date of first study treatment to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.

End point type

Secondary

End point timeframe

Date of First Study Treatment to Measured Progressive Disease or Death (Up to 35 Months) APD: All participants who received at least one dose of study drug in the Phase 2 cohorts. Censored participants Galunisertib + Nivolumab (NSCLC) Phase 2 = 6.

Notes
[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: Per protocol, anti-tumor activity was assessed only on Phase 2 participants.

End point values	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	25	1 ^[5]
Units: months
median (confidence interval 95%)	5.26 (1.77 to 9.20)	0 (0 to 0)

Notes
[5] - N=1: Median: 5.39, CI: not evaluable (NE)

No statistical analyses for this end point

Secondary: Phase 2: Percentage of Participants who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR)

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End point title

Phase 2: Percentage of Participants who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR) ^[6]

End point description

Objective Response Rate was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.

End point type

Secondary

End point timeframe

Baseline to Measured Progressive Disease (Up to 35 Months)

Notes
[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: Per protocol, anti-tumor activity was assessed only on Phase 2 participants.

End point values	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	25 ^[7]	1 ^[8]
Units: Percentage of Participants
number (not applicable)	24.0	0.0

Notes
[7] - APD: All participants who received at least one dose of study drug in Phase 2 cohorts.
[8] - APD: All participants who received at least one dose of study drug in Phase 2 cohorts.

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DoR)

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End point title

Phase 2: Duration of Response (DoR) ^[9]

End point description

Duration of response is measured from the date of documented response to the date of first progression of disease or the date of death due to any cause, whichever is earlier. APD: All participants who received at least one dose of study drug in Phase 2 cohorts and had a response of complete response or partial response. Censored participants Galunisertib + Nivolumab (NSCLC) Phase 2 = 1.

End point type

Secondary

End point timeframe

Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 35 Months)

Notes
[9] - 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: Per protocol, anti-tumor activity was assessed only on Phase 2 participants.

End point values	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	6	1 ^[10]
Units: months
median (full range (min-max))	9.03 (1.97 to 35)	0 (0 to 0)

Notes
[10] - There was no response to treatment for the HCC cohort.

No statistical analyses for this end point

Secondary: Phase 2: Time to Response

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End point title

Phase 2: Time to Response ^[11]

End point description

Time to response was measured from the date of first study treatment to the first documented response of Complete Response (CR) or Partial Response (PR). APD: All participants who received at least one dose of study drug in Phase 2 cohorts and had a documented response of CR or PR.

End point type

Secondary

End point timeframe

Date of First Study Treatment to Date of Complete Response or Partial Response (Up to 35 Months)

Notes
[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: Per protocol, anti-tumor activity was assessed only on Phase 2 participants.

End point values	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	6	0 ^[12]
Units: months
median (full range (min-max))	4.2 (0.5 to 35)	( to )

Notes
[12] - There was no response to treatment for the HCC reporting group.

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[13]

End point description

Overall Survival is determined from the date of first study treatment until death due to any cause. APD: All participants who received at least one dose of study drug in Phase 2 cohorts. Censored participants Galunisertib + Nivolumab (NSCLC) Phase 2 = 8.

End point type

Secondary

End point timeframe

Date of First Study Treatment to Death from Any Cause (Up to 35 Months)

Notes
[13] - 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: Per protocol, anti-tumor activity was assessed only on Phase 2 participants.

End point values	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Number of subjects analysed	25	1 ^[14]
Units: months
median (confidence interval 95%)	11.99 (8.15 to 16.23)	0 (0 to 0)

Notes
[14] - N=1 median 14.52 months, CI is non-evaluable.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 34 Months

Adverse event reporting additional description

All participants who received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Galunisertib + Nivolumab (Cohort 1) Phase 1b

Reporting group description

50 mg Galunisertib administered orally QD on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV every Q2W on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Reporting group title

Galunisertib + Nivolumab (Cohort 2) Phase 1b

Reporting group description

50 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Reporting group title

Galunisertib + Nivolumab (Cohort 3) Phase 1b

Reporting group description

80 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Reporting group title

Galunisertib + Nivolumab (Cohort 4) Phase 1b

Reporting group description

150 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV Q2W on Day 1 and Day 15 for 2 cycles. Participants may continue to receive study drug until discontinuation criteria are met.

Reporting group title

Galunisertib + Nivolumab (NSCLC) Phase 2

Reporting group description

Reporting group title

Galunisertib + Nivolumab (HCC) Phase 2

Reporting group description

Serious adverse events	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	2 / 5 (40.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	13 / 25 (52.00%)	0 / 1 (0.00%)
number of deaths (all causes)	0	0	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
adenocarcinoma of colon
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	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
Vascular disorders
angiopathy
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
acute myocardial infarction
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
pericarditis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
cerebrovascular accident
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	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
headache
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
noninfective encephalitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
chest pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
dyspepsia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
large intestinal obstruction
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
small intestinal obstruction
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	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
vomiting
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	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
Hepatobiliary disorders
cholestasis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
cough
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	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
dyspnoea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
respiratory failure
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
hydronephrosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 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
pain in extremity
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Infections and infestations
bronchitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
lower respiratory tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pneumonia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pyelonephritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
respiratory tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
septic shock
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
urinary tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
dehydration
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
failure to thrive
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	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

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Galunisertib + Nivolumab (Cohort 1) Phase 1b	Galunisertib + Nivolumab (Cohort 2) Phase 1b	Galunisertib + Nivolumab (Cohort 3) Phase 1b	Galunisertib + Nivolumab (Cohort 4) Phase 1b	Galunisertib + Nivolumab (NSCLC) Phase 2	Galunisertib + Nivolumab (HCC) Phase 2
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	4 / 5 (80.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	23 / 25 (92.00%)	1 / 1 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
tumour pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
Vascular disorders
hot flush
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	5	0
hypertension
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
hypotension
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0
jugular vein thrombosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
phlebitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
General disorders and administration site conditions
asthenia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	5	0
chest pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
chills
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
fatigue
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	6 / 25 (24.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	10	0
influenza like illness
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
malaise
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
multiple organ dysfunction syndrome
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
non-cardiac chest pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	1	0
oedema peripheral
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pyrexia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	5 / 25 (20.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	8	0
Respiratory, thoracic and mediastinal disorders
aphonia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
bronchial fistula
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
bronchospasm
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
chronic obstructive pulmonary disease
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
cough
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	4	0
dysphonia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
dyspnoea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	2	0
haemoptysis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	1	0
oropharyngeal pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pleural effusion
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pneumonitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
productive cough
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pulmonary embolism
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0	0	0
respiratory acidosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
rhinitis allergic
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
rhinorrhoea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	1
Psychiatric disorders
depression
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	0	0
disorientation
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
insomnia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	1	1	0
Investigations
alanine aminotransferase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	3	4	0
amylase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 4 (75.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	6	2	0
aspartate aminotransferase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	4	4	0
blood alkaline phosphatase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	4	1	0
blood creatinine increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
cd4 lymphocytes decreased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
cystatin c increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
gamma-glutamyltransferase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	4	2	0
lipase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	7	1	0
lymphocyte count decreased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	3	0	0
neutrophil count decreased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	0	0
platelet count decreased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	3	0
transaminases increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
troponin t increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
weight decreased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
white blood cell count decreased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	3	0	0
Injury, poisoning and procedural complications
infusion related reaction
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
cardiac failure
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
mitral valve incompetence
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pericarditis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
sinus tachycardia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	0	0
Nervous system disorders
aura
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
dizziness
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0
epilepsy
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
headache
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	5 / 25 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	1	6	0
hypersomnia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
neurological decompensation
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
neurological symptom
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
neuropathy peripheral
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
paraesthesia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
peripheral motor neuropathy
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
somnolence
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood and lymphatic system disorders
anaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	3	3	0
disseminated intravascular coagulation
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
eosinophilia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
Ear and labyrinth disorders
tinnitus
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
Eye disorders
cataract
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
dry eye
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
Gastrointestinal disorders
abdominal distension
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	6	0
abdominal pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	1	0
cheilitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
constipation
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	5	0
diarrhoea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	2 / 5 (40.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	7 / 25 (28.00%)	0 / 1 (0.00%)
occurrences all number	1	5	0	1	10	0
dry mouth
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	5	0
dyspepsia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
dysphagia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
flatulence
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	3	0
gastrooesophageal reflux disease
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
haematemesis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	0	0
lower gastrointestinal haemorrhage
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
nausea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	1 / 5 (20.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	6 / 25 (24.00%)	0 / 1 (0.00%)
occurrences all number	1	1	1	2	6	0
oesophageal spasm
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
oral pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
rectal haemorrhage
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
stomatitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0
vomiting
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	2 / 3 (66.67%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	2	0	2	0	3	0
Hepatobiliary disorders
cholestasis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
Skin and subcutaneous tissue disorders
dermatitis acneiform
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	3	0
dry skin
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	3	0
hyperhidrosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
livedo reticularis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pruritus
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	9 / 25 (36.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	2	14	0
rash
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	4	0
rash maculo-papular
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	5 / 25 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	10	0
skin lesion
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
Renal and urinary disorders
acute kidney injury
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
dysuria
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
Endocrine disorders
hyperthyroidism
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
hypothyroidism
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	4	0
Musculoskeletal and connective tissue disorders
arthralgia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	3	0
arthritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	8	0
back pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 25 (24.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	6	0
bone pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
flank pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
gouty arthritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
muscular weakness
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
musculoskeletal chest pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
musculoskeletal pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	1	0
myalgia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
neck pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	2	0
pain in extremity
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0
Infections and infestations
cellulitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0
escherichia infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
gingivitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	1
influenza
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
otitis externa
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
otitis media
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
pneumonia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0
respiratory tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0
rhinitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
skin infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
upper respiratory tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 25 (16.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	4	0
urinary tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	4	0
Metabolism and nutrition disorders
cachexia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0
decreased appetite
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	7 / 25 (28.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	1	11	0
dehydration
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	1 / 3 (33.33%)	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	0	0
hypercalcaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 25 (4.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0
hyperglycaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	3 / 25 (12.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	3	0
hyperkalaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0
hypertriglyceridaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0
hypoalbuminaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	3	0	0
hypocalcaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 25 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	5	0	0
hypokalaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	2	0
hypomagnesaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	2	0
hypophosphataemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 3 (0.00%)	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 25 (8.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	2	0

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Were there any global substantial amendments to the protocol? Yes

24 Jul 2015

Amendment A: • Addition of 2 cohorts • Addition of study ECG’s • Addition of ≥ CTCAE Grade 3 thrombocytopenia • Addition of serum pregnancy test on Day 1 of every cycle • Added ECHO at the 30-day follow-up visit • Additional patient enrolled predose level to allow for unforeseen discontinuation

30 Aug 2016

Amendment B: Removed high-sensitivity C-reactive protein

31 Jan 2017

Amendment C: Removal of glioblastoma cohort • Requirement for ECHO at the 30-day follow-up visit added back in protocol (c) • Add hepatitis B surface antigen testing back in protocol (c)

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.

Due low enrollment, the HCC cohort was terminated early.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Maximum Tolerated Dose (MTD) of Galunisertib in Combination with Nivolumab

Primary: Phase 1b: Maximum Tolerated Dose (MTD) of Galunisertib in Combination with Nivolumab

Secondary: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab

Secondary: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab

Secondary: PK: Area Under the Plasma Concentration -Time Curve of Galunisertib From Time Zero to 24 Hours (AUC [0-24h]) at Steady State

Secondary: PK: Area Under the Plasma Concentration -Time Curve of Galunisertib From Time Zero to 24 Hours (AUC [0-24h]) at Steady State

Secondary: Number of Participants with Anti-Nivolumab Antibodies When Administered in Combination with Galunisertib

Secondary: Number of Participants with Anti-Nivolumab Antibodies When Administered in Combination with Galunisertib

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Percentage of Participants who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR)

Secondary: Phase 2: Percentage of Participants who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR)

Secondary: Phase 2: Duration of Response (DoR)

Secondary: Phase 2: Duration of Response (DoR)

Secondary: Phase 2: Time to Response

Secondary: Phase 2: Time to Response

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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