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Clinical Trial Results:
A Randomized, Placebo-controlled, Double-blind, Multicenter Phase II Trial of Intravenous GC33 at 1600 mg Q2W in Previously Treated Patients with Unresectable Advanced or Metastatic Hepatocellular Carcinoma (HCC)

Summary
EudraCT number	2011-003574-84
Trial protocol	BE GB ES DE IT
Global end of trial date	20 Aug 2015

Results information
Results version number	v2(current)
This version publication date	02 Feb 2020
First version publication date	18 Jul 2015
Other versions	v1 (removed from public view)
Version creation reason

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

NP27884

ISRCTN number

US NCT number

NCT01507168

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

20 Aug 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Aug 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of this study was to evaluate the efficacy of GC33 in previously treated subjects with unresectable advanced or metastatic hepatocellular carcinoma.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Feb 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

42 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

France: 24

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Italy: 16

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

Hong Kong: 10

Country: Number of subjects enrolled

Japan: 23

Country: Number of subjects enrolled

Korea, Republic of: 19

Country: Number of subjects enrolled

Singapore: 3

Country: Number of subjects enrolled

Taiwan: 18

Country: Number of subjects enrolled

New Zealand: 2

Country: Number of subjects enrolled

United States: 21

Country: Number of subjects enrolled

United Kingdom: 12

Worldwide total number of subjects

185

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)

101

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 6 European, 5 Asian countries, New Zealand and the USA.

Screening details

Subjects with previously treated unresectable advanced or metastatic hepatocellular carcinoma (HCC) with tumour expression of GPC3 determined on tumour biopsy were randomised in a GC33:placebo ratio of 2:1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects were administered matching placebo on Days 1 and 8, and every 2 weeks thereafter.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous (IV) infusion of matching placebo was administered on Days 1 and 8, and every 2 weeks thereafter.

GC33

Arm description

Subjects were administered GC33 on Days 1 and 8, and every 2 weeks thereafter.

Arm type

Experimental

Investigational medicinal product name

GC33

Investigational medicinal product code

Other name

RO5137382

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous (IV) infusion of 1600 mg GC33 was administered on Days 1 and 8, and every 2 weeks thereafter.

Number of subjects in period 1	Placebo	GC33
Started	60	125
Safety Population	60	121
Completed	60	121
Not completed	0	4
Did not receive study medication	-	4

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects were administered matching placebo on Days 1 and 8, and every 2 weeks thereafter.

Reporting group title

GC33

Reporting group description

Subjects were administered GC33 on Days 1 and 8, and every 2 weeks thereafter.

Reporting group values	Placebo	GC33	Total
Number of subjects	60	125	185
Age Categorical
Units: Subjects
Age Continuous
All Randomised subjects were included.
Units: years
arithmetic mean (standard deviation)	61.0 ( 11.1 )	61.9 ( 11.9 )	-
Gender Categorical
All Randomised subjects were included.
Units: Subjects
Female	15	19	34
Male	45	106	151

End points

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Reporting group title

Placebo

Reporting group description

Subjects were administered matching placebo on Days 1 and 8, and every 2 weeks thereafter.

Reporting group title

GC33

Reporting group description

Subjects were administered GC33 on Days 1 and 8, and every 2 weeks thereafter.

Subject analysis set title

Cohort A (GPC3 IHC 2+/3+): Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

GPC3 IHC 2+/3+ subjects were administered matching placebo on Days 1 and 8, and every 2 weeks thereafter.

Subject analysis set title

Cohort A (GPC3 IHC 2+/3+): GC33

Subject analysis set type

Sub-group analysis

Subject analysis set description

GPC3 IHC 2+/3+ subjects were administered GC33 on Days 1 and 8, and every 2 weeks thereafter.

Subject analysis set title

Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

This included subjects from both cohort A (GPC3 IHC 2+/3+) and cohort B (GPC3 IHC 1+). The subjects were administered matching placebo on Days 1 and 8, and every 2 weeks thereafter.

Subject analysis set title

Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): GC33

Subject analysis set type

Sub-group analysis

Subject analysis set description

his included subjects from both cohort A (GPC3 IHC 2+/3+) and cohort B (GPC3 IHC 1+). The subjects were administered GC33 on Days 1 and 8, and every 2 weeks thereafter.

Primary: Progression-free Survival (PFS)

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End point title

Progression-free Survival (PFS)

End point description

PFS was defined as time between randomization and the first documentation of progression by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria or death (if death occurs earlier than progression). Disease progression was defined as at least a 20% increase in the sum of the longest diameter (LD) of the target lesions (TLs), taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more new lesions or unequivocal progression of existing non-target lesions. Participants who did not progress or die were censored on the date of the last valid tumor assessment. For participants who had no tumor assessment and no clinical progression post baseline and who did not die, PFS was assigned a value of one day and was censored in the analysis.

End point type

Primary

End point timeframe

From the time of randomisation up to progression or death, whichever occurred first up to the cut-off date for the analysis of 13 June 2013 (up to approximately 16 months)

End point values	Placebo	GC33	Cohort A (GPC3 IHC 2+/3+): Placebo	Cohort A (GPC3 IHC 2+/3+): GC33	Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): Placebo	Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): GC33
Number of subjects analysed	60	125	35	70	55	106
Units: Months
median (confidence interval 95%)	1.5 (1.5 to 2.8)	2.6 (1.5 to 3.0)	1.5 (1.4 to 2.8)	2.6 (1.4 to 3.7)	1.6 (1.5 to 2.8)	2.6 (1.5 to 3.0)

Placebo vs GC33

Comparison groups

Placebo v GC33

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8667

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.39

Cohort Placebo vs Cohort A: GC33

Comparison groups

Cohort A (GPC3 IHC 2+/3+): Placebo v Cohort A (GPC3 IHC 2+/3+): GC33

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9885

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

1.64

Cohort A+B: Placebo vs Cohort A+B: GC33

Comparison groups

Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): Placebo v Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): GC33

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9313

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.45

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as the interval of time from randomization to date of death due to any cause. Participants who were alive at the time of analysis were censored at the last documented date that they were known to be alive. Participants without follow up assessment were censored at the day of last dose and the participants with no post baseline information were censored at the date of randomization.

End point type

Secondary

End point timeframe

From the time of randomization to the date of death due to any cause up to the cut-off date for the analysis of 11 April 2014 (up to approximately 26 months)

End point values	Placebo	GC33	Cohort A (GPC3 IHC 2+/3+): Placebo	Cohort A (GPC3 IHC 2+/3+): GC33	Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): Placebo	Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): GC33
Number of subjects analysed	60	125	35	70	55	106
Units: months
median (confidence interval 95%)	10.0 (5.9 to 11.2)	8.7 (6.8 to 11.3)	6.7 (5.3 to 11.4)	8.9 (6.8 to 11.8)	7.6 (5.8 to 11.4)	8.9 (7.4 to 11.8)

No statistical analyses for this end point

Secondary: Time to progression (TTP)

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End point title

Time to progression (TTP)

End point description

TTP was defined as the time from randomization to the first documented disease progression. Only radiologically documented progression of tumor was considered as disease progression. Clinical progression as judged by the investigators was not considered as progressive disease, unless accompanied by radiological progression.

End point type

Secondary

End point timeframe

From the time of randomization to disease progression up to the cut-off date for the analysis of 13 June 2013 (up to approximately 16 months)

End point values	Placebo	GC33	Cohort A (GPC3 IHC 2+/3+): Placebo	Cohort A (GPC3 IHC 2+/3+): GC33	Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): Placebo	Cohort A (GPC3 IHC 2+/3+)+B (GPC3 IHC 1+): GC33
Number of subjects analysed	60	125	35	70	55	106
Units: months
median (confidence interval 95%)	1.7 (1.5 to 2.8)	2.9 (1.5 to 3.6)	1.9 (1.5 to 2.8)	2.9 (1.4 to 3.9)	1.9 (1.5 to 2.8)	2.8 (1.5 to 3.6)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title

Disease Control Rate (DCR)

End point description

The DCR was defined as the percentage of participants who had a best response of complete response (CR), partial Response (PR), or stable disease (SD) lasting at least 6 weeks. CR was defined as the disappearance of all target lesions; for non-target lesions disappearance of lesions and normal tumour marker levels. PR was defined as at least a 30% decrease in the sum of LD of target lesions, using as reference the Baseline sum LD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started; for non-target lesions persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.

End point type

Secondary

End point timeframe

From the time of randomization to disease progression up to the cut-off date for the analysis of 13 June 2013 (up to approximately 16 months)

End point values	Placebo	GC33
Number of subjects analysed	60	125
Units: percentage of subjects
number (not applicable)	38.3	43.2

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events (AEs)

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End point title

Number of Subjects With Adverse Events (AEs)

End point description

An adverse event (AE) was defined as any untoward medical occurrence in a participant who was administered a study treatment, regardless of whether or not the event had a causal relationship with the treatment. An AE, therefore, could be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study treatment, whether or not related to the treatment. The safety population included all subjects who received at least one dose or part of one dose of study medication.

End point type

Secondary

End point timeframe

Up to approximately 42 months

End point values	Placebo	GC33
Number of subjects analysed	60	121
Units: subjects	59	114

No statistical analyses for this end point

Secondary: Maximum Serum Concentration (Cmax) of GC33

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End point title

Maximum Serum Concentration (Cmax) of GC33 ^[1]

End point description

The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycles 1 and 6, Day 1: prior to infusion, end of infusion, at 24 hours (h) and 96 h (approximately first 40 subjects) or at 48 h (sparse sampling after first 40 subjects).

Notes
[1] - 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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	119
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1 (n=119)	515 ( 140 )
Cycle 6 (n=56)	715 ( 212 )

No statistical analyses for this end point

Secondary: Trough Serum Concentration (Cmin) of GC33

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End point title

Trough Serum Concentration (Cmin) of GC33 ^[2]

End point description

The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 8 and Cycle 7, Day 1: prior to infusion

Notes
[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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	12
Units: mcg/ml
arithmetic mean (standard deviation)
Cycle 1	175 ( 56.0 )
Cycle 6	258 ( 97.9 )

No statistical analyses for this end point

Secondary: Time to Reach Maximum Serum Concentration (Tmax) of GC33

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End point title

Time to Reach Maximum Serum Concentration (Tmax) of GC33 ^[3]

End point description

The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycles 1 and 6, Day 1: prior to infusion, end of infusion, at 24 h and 96 h (approximately first 40 subjects) or at 48 h (sparse sampling after first 40 subjects).

Notes
[3] - 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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	119
Units: day
median (full range (min-max))
Cycle 1 (n=119)	0.0722 (0.00 to 8.98)
Cycle 6 (n=56)	0.116 (0.00 to 1.15)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve to Last Measurable Concentration (AUClast) of GC33

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End point title

Area Under the Concentration-time Curve to Last Measurable Concentration (AUClast) of GC33 ^[4]

End point description

AUClast is the area under the concentration-time curve from time of dosing to the last measurable concentration from the same Cycle. The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycles 1 and 6, Day 1: prior to infusion, end of infusion, at 24 h and 96 h (approximately first 40 subjects) or at 48 h (sparse sampling after first 40 subjects).

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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	119
Units: day*mcg/ mL
arithmetic mean (standard deviation)
Cycle 1 (n=119)	1980 ( 649 )
Cycle 6 (n=14)	6420 ( 2060 )

No statistical analyses for this end point

Secondary: Clearance (CL) of GC33

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End point title

Clearance (CL) of GC33 ^[5]

End point description

The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 1: prior to infusion, end of infusion, at 24 h and 96 h.

Notes
[5] - 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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	5
Units: mL/day
arithmetic mean (standard deviation)
Cycle 1	889 ( 407 )

No statistical analyses for this end point

Secondary: Volume of Distribution (Vz) of GC33

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End point title

Volume of Distribution (Vz) of GC33 ^[6]

End point description

Cycle 1, Day 1: prior to infusion, end of infusion, at 24 h and 96 h. The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 1: prior to infusion, end of infusion, at 24 h and 96 h

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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	5
Units: mL
arithmetic mean (standard deviation)
Cycle 1	4200 ( 1000 )

No statistical analyses for this end point

Secondary: Accumulation Ratio for Cmax of GC33

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End point title

Accumulation Ratio for Cmax of GC33 ^[7]

End point description

Accumulation ratio for Cmax was calculated as Cmax observed at steady state in Cycle 6 divided by Cmax after first dose in Cycle 1. The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycles 1 and 6, Day 1: prior to infusion, end of infusion, at 24 hours (h) and 96 h (approximately first 40 subjects) or at 48 h (sparse sampling after first 40 subjects).

Notes
[7] - 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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	56
Units: unitless ratio
arithmetic mean (standard deviation)	1.42 ( 0.482 )

No statistical analyses for this end point

Secondary: Accumulation Ratio for AUC(0-8 days) of GC33

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End point title

Accumulation Ratio for AUC(0-8 days) of GC33 ^[8]

End point description

Accumulation ratio for AUC(0-8 days) was calculated as AUC(0-8 days) at steady state in Cycle 6 divided by AUC(0-8 days) after first dose in Cycle 1. The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycles 1 and 6, Day 1: prior to infusion, end of infusion, at 24 h and 96 h (approximately first 40 subjects) or at 48 h (sparse sampling after first 40 subjects), Cycles 1 and 6, Day 8.

Notes
[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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	12
Units: unitless ratio
arithmetic mean (standard deviation)	1.93 ( 0.330 )

No statistical analyses for this end point

Secondary: Accumulation Ratio for Cmin of GC33

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End point title

Accumulation Ratio for Cmin of GC33 ^[9]

End point description

Accumulation ratio for Cmin was calculated as Cmax observed at steady state prior to infusion at Cycle 7, Day divided by Cmax after first dose and prior to infusion at in Cycle 1, Day 8. The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 8 and Cycle 7, Day 1: prior to infusion.

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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	12
Units: unitless ratio
arithmetic mean (standard deviation)	1.59 ( 0.841 )

No statistical analyses for this end point

Secondary: Terminal Elimination Half-life (t1/2) of GC33

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End point title

Terminal Elimination Half-life (t1/2) of GC33 ^[10]

End point description

The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 1: prior to infusion, end of infusion, at 24 hours (h) and 96 h (approximately first 40 subjects) or at 48 h (sparse sampling after first 40 subjects) and prior to next infusion Cycle 1, Day 8.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	5
Units: day
arithmetic mean (standard deviation)
Cycle 1	3.74 ( 1.39 )

No statistical analyses for this end point

Secondary: Serum Concentration of GC33 at the Time of Tumor Progression (Cprog)

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End point title

Serum Concentration of GC33 at the Time of Tumor Progression (Cprog) ^[11]

End point description

The PK evaluable population included subjects who received at least one dose of GC33 and provided at least PK samples up to Day 3 of Cycle 1.

End point type

Secondary

End point timeframe

Cycle 1, Day 8 to Cycle 18, Day 1

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: Pharmacokinetic endpoint is only reported for the arm treated with GC33.

End point values	GC33
Number of subjects analysed	8
Units: mcg/mL
arithmetic mean (standard deviation)	135 ( 87.6 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to approximately 42 months

Adverse event reporting additional description

The safety population included all subjects who received at least one dose or part of one dose of study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Placebo

Reporting group description

Subjects were administered matching placebo on Days 1 and 8, and every 2 weeks thereafter.

Reporting group title

GC33

Reporting group description

Subjects were administered GC33 on Days 1 and 8, and every 2 weeks thereafter.

Serious adverse events	Placebo	GC33
Total subjects affected by serious adverse events
subjects affected / exposed	19 / 60 (31.67%)	32 / 121 (26.45%)
number of deaths (all causes)	42	76
number of deaths resulting from adverse events	3	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic Pain
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour Rupture
subjects affected / exposed	1 / 60 (1.67%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertensive Crisis
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General Physical Health Deterioration
subjects affected / exposed	1 / 60 (1.67%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	1 / 1	1 / 1
Generalised Oedema
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza Like Illness
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury Associated With Device
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 60 (5.00%)	5 / 121 (4.13%)
occurrences causally related to treatment / all	0 / 3	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Completed Suicide
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Investigations
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood Bilirubin Increased
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion Related Reaction
subjects affected / exposed	0 / 60 (0.00%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Radius Fracture
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial Fibrillation
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral Haemorrhage
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous System Disorder
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy Peripheral
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 60 (3.33%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile Neutropenia
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	1 / 60 (1.67%)	3 / 121 (2.48%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal Pain Upper
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 60 (1.67%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric Haemorrhage
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Gastric Ulcer Haemorrhage
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 60 (0.00%)	2 / 121 (1.65%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic Haemorrhage
subjects affected / exposed	2 / 60 (3.33%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice Cholestatic
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	1 / 60 (1.67%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	1 / 1
Nephrolithiasis
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tubulointerstitial Nephritis
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back Pain
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myopathy
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchopneumonia
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 60 (1.67%)	0 / 121 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis Bacterial
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 60 (0.00%)	3 / 121 (2.48%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Streptococcal Infection
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 60 (0.00%)	1 / 121 (0.83%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	GC33
Total subjects affected by non serious adverse events
subjects affected / exposed	52 / 60 (86.67%)	105 / 121 (86.78%)
Vascular disorders
Hot Flush
subjects affected / exposed	3 / 60 (5.00%)	0 / 121 (0.00%)
occurrences all number	3	0
Hypertension
subjects affected / exposed	6 / 60 (10.00%)	6 / 121 (4.96%)
occurrences all number	6	7
Nervous system disorders
Headache
subjects affected / exposed	2 / 60 (3.33%)	20 / 121 (16.53%)
occurrences all number	2	24
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 60 (5.00%)	6 / 121 (4.96%)
occurrences all number	4	9
General disorders and administration site conditions
Asthenia
subjects affected / exposed	12 / 60 (20.00%)	13 / 121 (10.74%)
occurrences all number	12	19
Chills
subjects affected / exposed	3 / 60 (5.00%)	12 / 121 (9.92%)
occurrences all number	4	12
Fatigue
subjects affected / exposed	12 / 60 (20.00%)	36 / 121 (29.75%)
occurrences all number	12	46
Influenza Like Illness
subjects affected / exposed	2 / 60 (3.33%)	9 / 121 (7.44%)
occurrences all number	2	11
Oedema Peripheral
subjects affected / exposed	8 / 60 (13.33%)	16 / 121 (13.22%)
occurrences all number	10	16
Pyrexia
subjects affected / exposed	6 / 60 (10.00%)	49 / 121 (40.50%)
occurrences all number	11	58
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	4 / 60 (6.67%)	5 / 121 (4.13%)
occurrences all number	4	5
Abdominal Pain
subjects affected / exposed	10 / 60 (16.67%)	15 / 121 (12.40%)
occurrences all number	11	15
Abdominal Pain Upper
subjects affected / exposed	2 / 60 (3.33%)	7 / 121 (5.79%)
occurrences all number	2	7
Ascites
subjects affected / exposed	6 / 60 (10.00%)	7 / 121 (5.79%)
occurrences all number	9	7
Constipation
subjects affected / exposed	9 / 60 (15.00%)	17 / 121 (14.05%)
occurrences all number	10	21
Diarrhoea
subjects affected / exposed	10 / 60 (16.67%)	18 / 121 (14.88%)
occurrences all number	14	19
Dyspepsia
subjects affected / exposed	3 / 60 (5.00%)	4 / 121 (3.31%)
occurrences all number	4	5
Nausea
subjects affected / exposed	5 / 60 (8.33%)	21 / 121 (17.36%)
occurrences all number	5	27
Vomiting
subjects affected / exposed	1 / 60 (1.67%)	15 / 121 (12.40%)
occurrences all number	1	17
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 60 (8.33%)	15 / 121 (12.40%)
occurrences all number	5	18
Dyspnoea
subjects affected / exposed	3 / 60 (5.00%)	9 / 121 (7.44%)
occurrences all number	3	9
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	6 / 60 (10.00%)	14 / 121 (11.57%)
occurrences all number	8	16
Psychiatric disorders
Insomnia
subjects affected / exposed	5 / 60 (8.33%)	7 / 121 (5.79%)
occurrences all number	5	7
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	8 / 60 (13.33%)	10 / 121 (8.26%)
occurrences all number	9	12
Musculoskeletal Chest Pain
subjects affected / exposed	3 / 60 (5.00%)	2 / 121 (1.65%)
occurrences all number	3	3
Myalgia
subjects affected / exposed	1 / 60 (1.67%)	7 / 121 (5.79%)
occurrences all number	1	7
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 60 (5.00%)	3 / 121 (2.48%)
occurrences all number	3	3
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	9 / 60 (15.00%)	19 / 121 (15.70%)
occurrences all number	9	28

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Were there any global substantial amendments to the protocol? Yes

14 Jun 2012

Amendment allowed an increase of the number of subjects in cohort C, GPC3-negative [IHC 0] from 6 to 21. These subjects were to be randomized in a 2:1 fashion (GC33: Placebo). Additional changes to the protocol: 1) Warning about non-steroidal anti-inflammatory drugs (NSAIDs) used; use of ibuprofen prohibited, 2) Submission of tumour tissue for GPC3 IHC could be done up to 4 weeks prior to the 28-day screening period (ICF must have been previously signed). Collection of the tumor tissue could be done within approximately 12 months (the sponsor to be contacted if the collection exceeded 12 months), 3) The QTc (machine reading) was not collected for the study. QTc to be calculated internally, 4) Timing of reporting of Serious Adverse Events and Pregnancy were updated, 5) Statistical Analyses were updated.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
20 Aug 2015	A protocol-specified analysis was triggered on 06 May 2013, after 128 progression-free survival events had been observed. This unblinded data review suggested that improved efficacy would not be observed, regardless of patients’ GPC3 expression level, after treatment with GC33. Consequently, treatment of the remaining subjects in the study was unblinded, and the study was stopped by the Sponsor. Although the study was discontinued, subjects were given the option to continue receiving treatment at the discretion of the Principal Investigator. One subject remained on treatment and continued to receive GC33 for an additional 16 months up to the global interruption date.	-

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 Randomized, Placebo-controlled, Double-blind, Multicenter Phase II Trial of Intravenous GC33 at 1600 mg Q2W in Previously Treated Patients with Unresectable Advanced or Metastatic Hepatocellular Carcinoma (HCC)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free Survival (PFS)

Primary: Progression-free Survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Time to progression (TTP)

Secondary: Time to progression (TTP)

Secondary: Disease Control Rate (DCR)

Secondary: Disease Control Rate (DCR)

Secondary: Number of Subjects With Adverse Events (AEs)

Secondary: Number of Subjects With Adverse Events (AEs)

Secondary: Maximum Serum Concentration (Cmax) of GC33

Secondary: Maximum Serum Concentration (Cmax) of GC33

Secondary: Trough Serum Concentration (Cmin) of GC33

Secondary: Trough Serum Concentration (Cmin) of GC33

Secondary: Time to Reach Maximum Serum Concentration (Tmax) of GC33

Secondary: Time to Reach Maximum Serum Concentration (Tmax) of GC33

Secondary: Area Under the Concentration-time Curve to Last Measurable Concentration (AUClast) of GC33

Secondary: Area Under the Concentration-time Curve to Last Measurable Concentration (AUClast) of GC33

Secondary: Clearance (CL) of GC33

Secondary: Clearance (CL) of GC33

Secondary: Volume of Distribution (Vz) of GC33

Secondary: Volume of Distribution (Vz) of GC33

Secondary: Accumulation Ratio for Cmax of GC33

Secondary: Accumulation Ratio for Cmax of GC33

Secondary: Accumulation Ratio for AUC(0-8 days) of GC33

Secondary: Accumulation Ratio for AUC(0-8 days) of GC33

Secondary: Accumulation Ratio for Cmin of GC33

Secondary: Accumulation Ratio for Cmin of GC33

Secondary: Terminal Elimination Half-life (t1/2) of GC33

Secondary: Terminal Elimination Half-life (t1/2) of GC33

Secondary: Serum Concentration of GC33 at the Time of Tumor Progression (Cprog)

Secondary: Serum Concentration of GC33 at the Time of Tumor Progression (Cprog)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Placebo-controlled, Double-blind, Multicenter Phase II Trial of Intravenous GC33 at 1600 mg Q2W in Previously Treated Patients with Unresectable Advanced or Metastatic Hepatocellular Carcinoma (HCC)