20060517

Amgen Inc.

One Amgen center Drive, Thousand Oaks, CA, United States, 91320

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

No

No

No

Final

19 Apr 2017

No

Yes

19 Apr 2017

No

The primary objective was to determine if trebananib plus pegylated liposomal doxorubicin (PLD) is superior to placebo plus PLD as measured by progression-free survival (PFS), defined as the time from randomization to the earliest of the dates of first radiologic disease progression per Response Evaluation Criteria in Solid Tumors 1.1 with modifications (RECIST 1.1 mod) or death from any cause in subjects with recurrent partially platinum sensitive or resistant epithelial ovarian, primary peritoneal or fallopian tube cancer.

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, United States Food and Drug Administration (FDA) regulations/guidelines, and country-specific national and local laws. A copy of the protocol, proposed informed consent form (ICF), other written subject information, and any proposed advertising material was submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for written approval. A copy of the IEC/IRB approval was received by the sponsor before recruitment of subjects into the study. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.

18 Apr 2011

Yes

Yes

Canada: 9

United States: 23

Australia: 11

Austria: 15

Belgium: 37

Denmark: 2

France: 4

Germany: 12

Italy: 37

New Zealand: 7

United Kingdom: 26

Hong Kong: 9

Hungary: 14

Poland: 3

Singapore: 5

Slovakia: 9

223

159

0

0

0

0

0

0

147

76

0

Overall Study (overall period)

Randomised - controlled

Yes

Placebo to Trebananib

Powder for solution for infusion

Intravenous use

Administered as an IV infusion

Trebananib

AMG 386

Powder for solution for infusion

Intravenous use

15 mg/kg administered as an IV infusion

Placebo + PLD

Trebananib + PLD

Placebo + PLD

Trebananib + PLD

PFS was defined as the time from the date of randomization to the earliest of the dates of first radiologic disease progression per RECIST 1.1 with modifications, based on investigator assessment, or death from any cause. Subjects who did not meet these criteria by the analysis data cutoff date had their PFS time censored at the latest of their last evaluable radiologic disease assessment date. Events of radiographic progression per RECIST 1.1 with modifications that occurred after initiation of subsequent anticancer therapy were not considered PFS events and were censored at the last evaluable radiographic tumor assessment before the initiation of subsequent anticancer therapy. Deaths that occurred after initiation of subsequent anticancer therapy were considered PFS events.

Primary

From randomization to the data cut off-date of 19 April 2017; median follow-up time was 15.2 months (interquartile range [IQR], 8.8-25.4) in the Placebo arm and 17.3 months (IQR, 8.4-27.7) in the Trebananib group

A stratified log-rank test was used for the primary comparison of PFS.

Trebananib + PLD v Placebo + PLD

223

Pre-specified

A stratified piecewise Cox regression model using 16-week intervals was used to estimate the PFS hazard ratio (HR) and 2-sided 95% confidence interval (CI) for trebananib in combination with PLD relative to placebo and PLD.

Placebo + PLD v Trebananib + PLD

223

Pre-specified

0.92

2-sided

Overall survival was defined as the time from the randomization date to the date of death from any cause. Subjects who did not die by the analysis data cutoff date were censored at their last contact date prior to the data cutoff date. Subjects known to be alive prior to the data cutoff date were censored at the last contact prior to the cutoff date. Subjects known to be alive or dead after the data cutoff date were censored at the data cutoff date.

Secondary

From randomization to the data cut off-date of 19 April 2017; median follow-up time was 15.2 months (interquartile range [IQR], 8.8-25.4) in the Placebo arm and 17.3 months (IQR, 8.4-27.7) in the Trebananib group.

A stratified log-rank test was used for the primary comparison of overall survival.

Placebo + PLD v Trebananib + PLD

223

Pre-specified

A stratified Cox regression model was also used to provide the estimated overall survival hazard ratio and 2-sided 95% CI for trebananib in combination with PLD relative to placebo and PLD.

Placebo + PLD v Trebananib + PLD

223

Pre-specified

1.04

2-sided

Disease response was assessed using computed tomography or magnetic resonance imaging of at least the chest, abdomen and pelvis. Objective response rate (ORR) was defined as the percentage of participants with measurable disease at baseline who achieved either a complete response (CR) or partial response (PR) while on study, according to RECIST 1.1 mod assessed by the investigator. CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the size of target lesions with persistence of one or more non-target lesions and no new lesions, or, disappearance of all target lesions with persistence of one or more non-target lesions and no new lesions. Participants with measurable disease at baseline who did not meet the criteria for objective response by the analysis cut-off date were considered non-responders.

Secondary

Disease response was assessed every 8 weeks for the first 64 weeks, then every 16 weeks for 32 weeks, and every 24 weeks thereafter until disease progression or death.

Placebo + PLD v Trebananib + PLD

193

Pre-specified

3.79

2-sided

Duration of response was defined as the time from the first objective response to disease progression per RECIST 1.1 with modifications or death due to any cause. Subjects not meeting criteria for disease progression by the analysis data cut-off date were censored at their last evaluable disease assessment date. The analysis of DOR was conducted on the subset of subjects with measurable disease at baseline who experienced an objective response during the study.

Secondary

Disease response was assessed every 8 weeks for the first 64 weeks, then every 16 weeks for 32 weeks, and every 24 weeks thereafter until disease progression or death.

A confirmed CA-125 response, according to the Gynecologic Cancer Intergroup (GCIG) criteria, defined as the percentage of participants with at least a 50% reduction in CA-125 levels from baseline, confirmed and maintained for at least 28 days. Only participants with CA-125 levels at least 2 X the upper limit of normal (ULN) within 2 weeks of starting treatment were evaluated for CA-125 response. Participants evaluable for CA-125 response that did not meet the criteria for a CA-125 response were considered non-responders.

Secondary

CA-125 was measured every 4 weeks for up to 2 years and then every 6 months thereafter.

Placebo + PLD v Trebananib + PLD

181

Pre-specified

3.05

2-sided

Secondary

Baseline and every 4 weeks for 2 years and then every 6 months thereafter until the end of treatment.

Adverse events were graded for severity using the Common Terminology Criteria for Adverse Events version 3.0. Trebananib/placebo-related or PLD-related adverse events are those events for which the investigator considered there to be a reasonable possibility that the event may have been caused by the study treatment, trebananib/placebo or PLD, respectively.

Secondary

From the first dose of study drug until 30 days after last dose; the median duration of trebananib treatment was 156 days.

Secondary

Week 1 and week 5 at the end of infusion

Secondary

Weeks 2, 5 and 9, predose

Two validated assays were used to detect the presence of anti-trebananib antibodies. Samples were first tested in a biosensor immunoassay to detect antibodies capable of binding to trebananib. Samples confirmed to be positive for binding antibodies were subsequently tested in a receptor-binding assay to determine neutralizing activity against trebananib. If a post-dose sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies.

Secondary

Pre-infusion of trebananib or placebo on day 1 of week 1, week 9 and at the safety follow-up visit.

The FACT-O evaluates the health-related quality of life (HRQOL) and symptoms in patients with ovarian cancer. It consists of the FACT-G, a 27 item general cancer questionnaire and a 12-item ovarian cancer-specific subscale (OCS). Each item is scored by the participant on a scale from 0 (not at all true) to 4 (very much true). The total score ranges from 0 to 156; a higher total score indicates better quality of life or less severe symptoms. The patient-reported outcomes (PRO) analysis set is defined as a subset of randomized subjects who have a baseline PRO assessment and at least one post-baseline PRO assessment prior to disease progression.

Secondary

Baseline and Weeks 5, 9, 13, 17, 25, 33, 41, 49, 57, 65, 81, and the safety follow-up visit 30 days after last dose.

The FACT-O evaluates the health-related quality of life (HRQOL) and symptoms in patients with ovarian cancer. It consists of the FACT-G, a 27 item general cancer questionnaire and a 12-item ovarian cancer-specific subscale (OCS). The OCS consists of 12 symptom items including swelling in stomach area, cramps in stomach area, weight loss, hair loss, control of bowels, appetite, vomiting, ability to get around, liking the appearance of one’s body, being able to feel like a woman, interest in sex, and concern about ability to have children. Each item is scored by the participant on a scale from 0 (not at all true) to 4 (very much true). The OCS summary score ranges from 0 to 48, where a higher score indicates better quality of life or less severe symptoms. The PRO analysis set includes a subset of randomized subjects who had a baseline PRO assessment and at least one post-baseline PRO assessment prior to disease progression.

Secondary

Baseline and Weeks 5, 9, 13, 17, 25, 33, 41, 49, 57, 65, 81, and the safety follow-up visit 30 days after last dose.

The EQ-5D is a standardized instrument for use as a generic, preference-based measure of health outcome. The EQ-5D questionnaire captures two basic types of information, a descriptive “profile,” or “health state,” and an overall health rating using a visual analogue scale. The health state includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each question has 3 answer choices: 1 (no problems), 2 (moderate problems), and 3 (extreme problems). The health states for each respondent are converted into a single index number using a specified set of weights. Resulting scores can range from 1.0 and –0.594. A higher score indicates a more preferred health status with 1.0 representing perfect health. The PRO analysis set includes a subset of randomized subjects who had a baseline assessment and at least 1 post-baseline PRO assessment prior to disease progression.

Secondary

Baseline and Weeks 5, 9, 13, 17, 25, 33, 41, 49, 57, 65, 81, and the safety follow-up visit 30 days after last dose.

The EQ-5D is a standardized instrument for use as a generic, preference-based measure of health outcome. The EQ-5D questionnaire captures two basic types of information, a descriptive “profile,” or “health state,” and an overall health rating using a visual analogue scale (VAS). The visual analogue scale asks respondents to rate their present health status on a 0 - 100 visual analogue scale, with 0 labeled as “Worst imaginable health state” and 100 labeled as “Best imaginable health state.” The VAS score is determined by observing the point at which the subjects hand drawn line intersects the scale. The PRO analysis set includes the subset of randomized subjects who had a baseline assessment and at least 1 post-baseline PRO assessment prior to disease progression.

Secondary

Baseline and Weeks 5, 9, 13, 17, 25, 33, 41, 49, 57, 65, 81, and the safety follow-up visit 30 days after last dose.

From the first dose of study drug until 30 days after last dose; the median duration of trebananib treatment was 156 days.

One subject randomized to the placebo group received trebananib and was counted in the trebananib group for safety analyses.

20.0

Trebananib + PLD

Placebo + PLD