20060342

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

09 Dec 2019

No

Yes

09 Dec 2019

No

The primary objective was to estimate the treatment effect as measured by progression-free survival (PFS) in subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer receiving trebananib (either 3 or 10 mg/kg intravenously [IV] once weekly [QW]) in combination with paclitaxel (80 mg/m² IV QW; 3 weeks on/1 week off) compared with subjects receiving paclitaxel (80 mg/m² IV QW; 3 weeks on/1 week off) plus placebo.

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol and amendments, the proposed informed consent form, and other written subject information were submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) of each study center for approval. A copy of the IEC/IRB approval was received by the sponsor before recruitment of subjects into the study and shipment of investigational product. Subjects or their legally authorized representatives were required to sign the informed consent form before any study-specific screening procedures were performed.

05 Jul 2007

Yes

No

Australia: 32

Belgium: 10

Canada: 40

India: 8

United States: 71

161

10

0

0

0

0

0

0

104

56

1

Overall Study (overall period)

Randomised - controlled

Yes

Tebananib

AMG 386

Concentrate for solution for infusion

Intravenous use

Administered by intravenous infusion over 60 minutes

Paclitaxel

Taxol®

Concentrate for solution for infusion

Intravenous use

Paclitaxel 80 mg/m² IV once a week (QW) (3 weeks on/1 week off) administered by intravenous infusion

Tebananib

AMG 386

Concentrate for solution for infusion

Intravenous use

Administered by intravenous infusion over 60 minutes

Paclitaxel

Taxol®

Concentrate for solution for infusion

Intravenous use

Paclitaxel 80 mg/m² IV once a week (QW) (3 weeks on/1 week off) administered by intravenous infusion

Placebo to trebananib

Concentrate for solution for infusion

Intravenous use

Administered by intravenous infusion over 60 minutes

Paclitaxel

Taxol®

Concentrate for solution for infusion

Intravenous use

Paclitaxel 80 mg/m² IV once a week (QW) (3 weeks on/1 week off) administered by intravenous infusion

Trebananib 3 mg/kg + Paclitaxel

Trebananib 10 mg/kg + Paclitaxel

Placebo + Paclitaxel

Pooled Trebananib + Paclitaxel

Participants received IV trebananib 3 mg/kg or 10 mg/kg once a week and paclitaxel 80 mg/m² IV QW (3 weeks on and then 1 week off) until progression, unacceptable toxicity, or withdrawal of consent.

Trebananib 3 mg/kg + Paclitaxel

Trebananib 10 mg/kg + Paclitaxel

Placebo + Paclitaxel

Pooled Trebananib + Paclitaxel

Participants received IV trebananib 3 mg/kg or 10 mg/kg once a week and paclitaxel 80 mg/m² IV QW (3 weeks on and then 1 week off) until progression, unacceptable toxicity, or withdrawal of consent.

Progression-free survival (PFS) was calculated using Kaplan-Meier methods as the time from the date of randomization to the earliest of the dates of first disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, clinical progression (per investigator), CA-125 progression per Gynecologic Cancer Intergroup (GCIG) criteria, or death from any cause. Participants not meeting these criteria by the analysis data cut-off date were censored at their last evaluable disease assessment date. Disease progression per RECIST was defined as at least a 20% increase in the size of target lesions, any new lesions and/or unequivocal progression of non-target lesions. CA-125 progression is defined as CA-125 ≥ 2 x upper limit of normal (ULN) for participants with baseline CA-125 < ULN, or CA-125 ≥ 2 x nadir value for participants with baseline CA-125 ≥ ULN, confirmed with a second sample no less than 28 days after the criteria for progression were first met.

Primary

From randomization to the final analysis data cut-off date of 09 December 2019; median time on follow-up was 89 weeks.

The primary analysis of PFS used a Cox regression model stratified by the stratification factors (prior VEGF therapy, disease progression on or within 6 months of the last chemotherapy regimen) to estimate the PFS hazard ratio and two-sided 80% confidence interval for comparison of both trebananib treatment groups (combined) versus placebo.

Placebo + Paclitaxel v Pooled Trebananib + Paclitaxel

161

Pre-specified

0.662

2-sided

Trebananib 10 mg/kg + Paclitaxel v Placebo + Paclitaxel

108

Pre-specified

0.661

2-sided

Trebananib 3 mg/kg + Paclitaxel v Placebo + Paclitaxel

108

Pre-specified

0.653

2-sided

Dose-response effects were tested using a Tarone’s test (stratified by the randomization factors) designed to assess improvement in PFS in at least 1 trebananib group versus placebo across the 3 treatment groups.

Trebananib 3 mg/kg + Paclitaxel v Trebananib 10 mg/kg + Paclitaxel v Placebo + Paclitaxel

161

Pre-specified

Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis was performed every 8 weeks during the study. Tumor responses per modified RECIST were determined by the investigator. Objective response rate (ORR) was defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) per modified RECIST criteria. Complete response: Disappearance of all target and non-target lesions, and no new lesions. Partial response: At least a 30% decrease in the size of target lesions with no new lesions or progression of non-target lesions, or, disappearance of all target lesions with persistence of one or more non-target lesions. Response must have been confirmed by consecutive assessments performed no less than 28 days after the criteria for response were first met.

Secondary

Assessed every 8 weeks throughout the study; analysis includes data up to the cut-off date of 09 December 2019; median time on follow-up was 89 weeks.

Duration of response was measured as the time from the first objective response (subsequently confirmed within no less than 4 weeks) to first observed disease progression per modified RECIST criteria or death due to any cause. Participants not meeting these criteria by the analysis data cut-off date were censored at their last evaluable disease assessment date. DOR was calculated using Kaplan-Meier methods. Disease progression per modified RECIST criteria was defined as at least a 20% increase in the size of target lesions, the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Secondary

From randomization to the data cut-off date of 9 December 2019; median time on follow-up was 89 weeks.

CA-125 PFS was calculated using Kaplan-Meier methods as the time from the randomization date to the earliest of the dates of first disease progression per CA-125 criteria or death from any cause. Participants not meeting these criteria by the analysis data cut-off date were censored at their last evaluable CA-125 assessment date. CA-125 progression is defined as CA-125 ≥ 2 × upper limit of normal (ULN) for participants with CA-125 < ULN at baseline, or CA-125 ≥ 2 × nadir value for participants with CA-125 ≥ ULN at baseline, confirmed with a second sample no less than 28 days after the criteria for progression were first met.

Secondary

From randomization until the primary analysis data cut-off date of 21 October 2009; median time on follow-up was 46 weeks.

CA-125 response rate is the the percentage of participants with a confirmed CA-125 response, defined as ≥ 50% reduction in CA-125 level from baseline, confirmed by a repeat sample no less than 28 days after the criteria for CA-125 response were first met. CA-125 response was analyzed in participants in the ITT population with baseline CA-125 level ≥ 2 × ULN (evaluable for CA-125 response analysis set).

Secondary

From randomization to the primary analysis cut-off date of 21 October 2009; median time on follow-up was 46 weeks.

Duration of CA-125 response was calculated only for those participants with a confirmed CA-125 response at the time of the primary analysis as the time from the first CA-125 response (subsequently confirmed within no less than 4 weeks) to first observed disease progression per CA-125 or death due to any cause. Participants not meeting these criteria by the analysis data cutoff date were censored at their last evaluable CA-125 assessment date. CA-125 progression is defined as CA-125 ≥ 2 x upper limit of normal (ULN) for participants with CA-125 < ULN at baseline, or CA-125 ≥ 2 x nadir value for participants with CA-125 ≥ ULN at baseline, confirmed with a second sample no less than 28 days after the criteria for progression were first met. 99999 indicates values that could not be estimated due to the low number of events.

Secondary

From randomization until the primary analysis data cut-off date of 21 October 2009; median time on follow-up was 46 weeks.

Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis was performed every 8 during the study. Maximum percent reduction in the sum of the longest diameters of target lesions was calculated as the maximum change from baseline to the post-baseline nadir.

Secondary

Baseline and every 8 weeks thereafter, up to the data cut-off date of 09 December 2019; median time on follow-up was 89 weeks.

Maximum percent reduction in CA-125 level was calculated as the maximum change from baseline to post-baseline nadir. Assays for CA-125 were performed every 8 weeks by both local and central laboratories.

Secondary

Baseline and every 8 weeks thereafter, up to the data cut-off date of 09 December 2019; median time on follow-up was 89 weeks.

Overall survival was calculated using Kaplan-Meier methods as the time from the randomization date to the date of death from any cause. Participants who had not died by the analysis data cut-off date were censored at their last contact date.

Secondary

From randomization to the final analysis data cut-off date of 09 December 2019; median time on follow-up was 89 weeks.

Time to progression (TTP) was calculated using Kaplan-Meier methods as the time from the randomization date to date of first observed disease progression per modified RECIST criteria, clinical progression, or CA-125 progression. Participants not meeting these criteria by the analysis data cut-off date were censored at their last evaluable disease assessment date. Disease progression per modified RECIST criteria was defined as at least a 20% increase in the size of target lesions, any new lesions and/or unequivocal progression of non-target lesions. CA-125 progression is defined as CA-125 ≥ 2 x ULN for participants with baseline CA-125 < ULN, or CA-125 ≥ 2 x nadir value for participants with baseline CA-125 ≥ ULN, confirmed with a second sample no less than 28 days after the criteria for progression were first met.

Secondary

From randomization until the primary analysis data cut-off date of 21 October 2009; median time on follow-up was 46 weeks.

Time to response was calculated in participants in the ITT population with measurable disease at baseline who had an objective response at the primary analysis data cut-off date of 21 October 2009 as the time from the randomization date to first objective response (subsequently confirmed within no less than 4 weeks).

Secondary

From randomization until the primary analysis data cut-off date of 21 October 2009; median time on follow-up was 46 weeks.

Time to CA-125 response was calculated in participants in the ITT population evaluable for CA-125 response who had a CA-125 response at the primary analysis data cut-off date of 21 October 2009 as the time from the randomization date to first CA-125 response (subsequently confirmed within no less than 4 weeks).

Secondary

From randomization until the primary analysis data cut-off date of 21 October 2009; median time on follow-up was 46 weeks.

FACT-O evaluates health-related quality of life (QOL) and symptoms in women with ovarian cancer. It consists of a 27-item general cancer questionnaire (FACT-G) and a 12-item ovarian cancer-specific subscale (OCS). The OCS summary score was calculated from the following 11 items: swelling in stomach area, cramps in stomach area, weight loss, hair loss, bowel control, appetite, vomiting, ability to get around, liking the appearance of one’s body, ability to feel like a woman, and interest in sex. Each item is scored from 0 to 4, such that a higher score indicates better QOL or less severe symptoms. The OCS summary score ranges from 0 to 44. A positive change from baseline indicates improvement. The overall change is the average across all the weeks analyzed in the model. The linear mixed model included fixed effects for treatment, timepoint, baseline score and interaction of timepoint and treatment and a random intercept for patient. 99999: no participants with data at this time point.

Secondary

Baseline and weeks 8, 16, 24, 32, 40, 48, and 56

The severity of each adverse event (AE) was graded according to the The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, or according to the following scale: 1 = mild 2 = moderate 3 = severe 4 = life-threatening 5 = fatal. A serious adverse event (SAE) is defined as an adverse event that • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • other significant medical hazard The the relationship of each AE to study treatment was assessed by the investigator.

Secondary

From first dose of any study drug to 30 days after last dose; median treatment duration for trebananib and paclitaxel was 156 and 153 days in the Trebananib 3 mg/kg arm, 166 and 155 days in the Trebananib 10 mg/kg arm, and 98 days each in the Placebo arm.

Samples were first tested in a validated electrochemiluminescent immunoassay to detect and confirm the presence of antibodies capable of binding to trebananib. Samples that were positive in the immunoassay were then further tested in a validated electrochemiluminescent receptor-binding assay to measure neutralizing or inhibitory effects of the antibodies in vitro. Developing anti-trebananib antibodies is defined as participants with a negative or no immunoassay result at or before baseline and a positive immunoassay result at a post-baseline timepoint, out of participants with at least one post-baseline immunoassay result. If a sample was positive in both assays, a participant was defined as positive for neutralizing antibodies.

Secondary

Predose at weeks 1, 5, and 9, and every 16 weeks thereafter, up to 5 weeks after the last dose of trebananib. Median treatment duration for trebananib/placebo was 156 days, 166 days, and 98 days in each treatment group respectively.

Serum trebananib concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the serum assay was 20 ng/mL. Cmax is the observed concentration at the end of infusion.

Secondary

Weeks 1 and 5 at end of infusion

Serum trebananib concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the serum assay was 20 ng/mL. Cmin is the observed concentration predose.

Secondary

Predose at weeks 3, 5, 9, 17, and 25

From first dose of any study drug to 30 days after last dose; median treatment duration for trebananib and paclitaxel was 156 and 153 days in the Trebananib 3 mg/kg arm, 166 and 155 days in the Trebananib 10 mg/kg arm, and 98 days each in the Placebo arm.

22.1

Trebananib 3 mg/kg + Paclitaxel

Placebo + Paclitaxel

Trebananib 10 mg/kg + Paclitaxel