CA182-033

Bristol-Myers Squibb

Chausée de la Hulpe 185, Brussels, Belgium, 1170

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com

No

No

No

Final

26 Sep 2013

No

Yes

26 Sep 2013

No

The primary objective of this study is to compare the Overall Survival (OS) of brivanib versus sorafenib in subjects with advanced HCC who have not received prior systemic treatment.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

19 May 2009

Yes

Yes

Argentina: 11

Australia: 15

Brazil: 124

Canada: 22

Hong Kong: 39

India: 97

Japan: 146

Korea, Republic of: 178

Mexico: 54

China: 249

Puerto Rico: 1

Russian Federation: 42

South Africa: 15

Taiwan: 204

Thailand: 59

Turkey: 21

United States: 51

Poland: 26

Spain: 6

Sweden: 7

United Kingdom: 66

Belgium: 1

Czech Republic: 28

France: 136

Germany: 28

Italy: 39

1665

337

0

0

0

0

0

0

1025

632

8

Treatment Period

Randomised - controlled

To maintain blinding of study treatment, study drugs were prepared in a double-dummy design using placebo matching the active treatments.

Yes

Sorafenib

Capsule

Oral use

Subjects were administered 400 mg of sorafenib capsules orally BID, 2*200-mg capsules in the AM and 2*200-mg capsules in the PM. Sorafenib was provided as gray, opaque, capsule shells.

Placebo

Tablet

Oral use

Subjects were administered four placebo matching brivanib alaninate tablets orally QD. Placebo brivanib alaninate tablets were provided as plain, white, biconvex, oval shaped film-coated tablets.

Brivanib alaninate

Tablet

Oral use

Subjects were administered 800 mg brivanib alaninate tablets (4*200 mg tablets) orally QD. Brivanib alaninate tablets were provided as plain, white, biconvex, oval shaped film-coated tablets.

Placebo

Capsule

Oral use

Subjects were administered four placebo matched sorafenib capsules orally BID, 2 capsules in the AM and 2 capsules in the PM. Sorafenib matched placebo was provided as gray, opaque, capsule shells.

Follow-up Period

Randomised - controlled

Yes

Placebo

Tablet

Oral use

No treatment was received in the follow-up, however, subjects were administered four placebo matching brivanib alaninate tablets orally QD in the treatment period.

Sorafenib

Capsule

Oral use

No treatment was received in the follow-up period , however, subjects were administered 400 mg of sorafenib capsules orally twice a day (BID) in the treatment period.

Placebo

Capsule

Oral use

No treatment was received in the follow-up. Subjects were administered four placebo matched sorafenib capsules orally BID in the treatment period.

Brivanib alaninate

Tablet

Oral use

No treatment was received in the follow-up, however, subjects were administered 800 mg brivanib alaninate tablets (4*200 mg tablets) orally QD in the treatment period.

Sorafenib

Brivanib

Sorafenib

Brivanib

Sorafenib

Brivanib

OS was computed for all per protocol subjects under non-inferiority test and was defined as time in months from the randomization date to the date of death due to any cause. If the subject did not die, survival was censored on the last date he or she was known to be alive. The analysis was performed in all the subjects in the per protocol population; all randomized subjects except for those who 1) had wrong diagnosis of cancer; 2) were not treated; 3) were not treated with the study therapy as assigned by the randomization. Non-inferiority of the brivanib-containing arms compared with the sorafenib-containing arms was investigated.

Primary

From randomization to death or date of last censoring (up to approximately 35 months)

Analysis compared survival in arms by stratified, 2-sided, alpha=0.05 level, log-rank test. Null hypothesis=survival was equal in both arms.

Sorafenib v Brivanib

1149

Pre-specified

1.06

2-sided

OS was computed for all randomized subjects under superiority test and was defined as time in months from the randomization date to the date of death due to any cause. If the subject did not die, survival was censored on the last date he or she was known to be alive. However, some subjects did not have a best overall response by investigators and were classified as unevaluable. The analysis was performed in all the subjects who were randomized to receive any study treatment. Superiority of the brivanib-containing arms compared with the sorafenib-containing arms was investigated.

Primary

From randomization to death or date of last censoring (up to approximately 35 months)

Analysis compared survival in arms by stratified, 2-sided, alpha=0.05 level, log-rank test. Null hypothesis=survival was equal in both arms. Power calculations indicated that >=817 deaths would lead to approximately 89% power at 5% level for rejecting null hypothesis, given a true hazard ratio of 0.80.

Brivanib v Sorafenib

1155

Pre-specified

1.07

2-sided

Time to progression was defined as the time from randomization to the time of radiographic disease progression. Subjects without progression were censored at their last tumor assessment date and those who had no on-study tumor assessment were censored at the date of randomization. TTP was based on tumor assessments made by the investigators according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for HCC, based on RECIST (version 1.0). mRECIST introduced the concept of the longest diameter of the viable tumor tissue for “typical” intrahepatic HCC lesions, those that displayed hypervascularity in the arterial phase and a wash-out in the portal or late venous phase in dynamic contrast-enhanced spiral CT or MRI. The analysis was performed in all randomized subjects; subjects randomized to any treatment, however some subjects did not have a best overall response by investigators and were classified as unevauable.

Secondary

From randomization to time of radiographic disease progression (up to approximately 31 months)

The primary comparison of TTP between treatment arms utilized a two-sided, = 0.05 level, stratified log-rank test (stratified by ECOG PS (0 vs 1), presence of extra-hepatic spread and/or vascular invasion (yes vs no) at the time of randomization and region (Asia vs Rest)).

Sorafenib v Brivanib

1155

Pre-specified

1.01

2-sided

ORR was defined as the proportion of randomized subjects in each treatment group whose best response was complete response (CR) or partial response (PR). DCR was defined as the proportion of randomized subjects in each treatment group whose best response was CR, PR, or stable disease (SD). ORR and DCR were assessed by the investigator using mRECIST criteria for HCC. Confidence intervals were based on the Clopper and Pearson method. The analysis was performed in all randomized subjects; subjects randomized to any treatment, however some subjects did not have a best overall response by investigators and were classified as unevaluable.

Secondary

From randomization to time of disease progression or death, whichever occurs first (up to approximately 35 months)

DCR compared treatment arms using a two-sided, = 0.05 level, Cochran-Mantel-Haenszel test with an associated odds ratio estimate and 95% confidence interval, stratified by ECOG Performance Status (0 vs 1), region (Asia vs Rest), extrahepatic spread and/or vascular invasion at randomization.

Sorafenib v Brivanib

1155

Pre-specified

1.02

2-sided

ORR compared treatment arms using a two-sided, = 0.05 level, Cochran-Mantel-Haenszel test with an associated odds ratio estimate and 95% confidence interval, stratified by ECOG Performance Status (0 vs 1), region (Asia vs Rest), extrahepatic spread and/or vascular invasion at randomization.

Sorafenib v Brivanib

1155

Pre-specified

1.45

2-sided

DOR was defined as the time from randomization to disease progression or death for randomized subjects whose best response was PR or CR. TTR was defined as the time from randomization to the time when response criteria was met for PR or CR, whichever occurred first. The DOR and TTR analysis was performed in all randomized subjects whose best response was CR or PR. Subjects who neither progressed nor died were censored on the date of their last tumor assessment.

Secondary

From randomization to time of disease progression or death, whichever occurs first (up to approximately 35 months)

Duration of disease control was defined as the time from randomization to disease progression or death for randomized subjects whose best response was PR, CR, or SD. The analysis was performed in all randomized subjects whose best response was PR, CR, or SD. Subjects who neither progressed nor died were censored on the date of their last tumor assessment.

Secondary

From randomization to time of disease progression or death, whichever occurs first (up to approximately 35 months)

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Grading per the National Cancer Institute Common Terminology Criteria (NCI CTC) Version 3.0 criteria. The analysis was performed in all treated subjects; subjects who received at least one dose of study medications. BMS excluded 27 subjects (9 from Taiwan per the Taiwan Food and Drug Administration [TFDA] Health Authority request and 18 from India due to unreliable data) from both the overall safety and efficacy analyses.

Secondary

Date of first dose of study drug to 30 days post last dose of study drug (up to approximately 35 months)

On Study (i.e. events from 1st dose date through last dose date + 30 days); up to approximately 35 months.

15.0

Brivanib

Sorafenib