Efficacy and Safety of Farletuzumab (MORAb-003) in Combination With Carboplatin and Taxane in Participants With Platinum-sensitive Ovarian Cancer in First Relapse

Study Overview
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Brief Summary
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This research is being done to find out if Carboplatin and Taxane works better alone or when given with an experimental drug called MORAb-003(farletuzumab) in subjects with first platinum sensitive relapsed ovarian cancer.

Official Title
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A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of Weekly Farletuzumab (MORAb-003) in Combination With Carboplatin and Taxane in Subjects With Platinum-sensitive Ovarian Cancer in First Relapse

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Farletuzumab
* Drug: Carboplatin
* Drug: Taxane
* Drug: Farletuzumab-matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A histologically or cytologically confirmed diagnosis of non-mucinous epithelial ovarian cancer including primary peritoneal or fallopian tube malignancies Must have measurable disease by CT or MRI scan Must have relapsed radiologically with a randomization date within ≥6 and < 24 months of completion of first-line platinum chemotherapy Have been treated with debulking surgery and first-line platinum and taxane based chemotherapy. Prior bevacizumbab maintenance is allowed. The last dose of bevacizumab must have been at least 30 days before study Day 1. No cytotoxic maintenance therapy (e.g. taxane) or cancer vaccine therapy is allowed. Must be a candidate for carboplatin and taxane therapy Neurologic function: neuropathy (sensory and motor) ≤CTCAE Grade 1 Exclusion Criteria: Subjects who never responded to first-line platinum-based therapy or whose first relapse occurs <6 months or >24 months from the last platinum therapy Subjects who have received other therapy to treat their ovarian cancer since relapse Known central nervous system (CNS) tumor involvement Evidence of other active invasive malignancy requiring treatment in the past 5 years Known allergic reaction to a prior monoclonal antibody therapy or have any documented HAHA Previous treatment with MORAb-003 (farletuzumab) Clinical contraindications to use of a taxane

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Farletuzumab (1.25 mg/kg)<br>Participants will receive farletuzumab 1.25 milligram per kilogram (mg/kg) administer as an intravenous (IV) infusion weekly, followed by taxane (paclitaxel [175 milligram per meter square {mg/m^2}] or docetaxel [75 mg/m^2]), administer as IV infusion and followed by carboplatin (to maintain area under curve [AUC] 5-6 milligram per milliliter per minute [mg/mL/minute]), administer as IV infusion, every three weeks, on Day 1 of each 21-day cycle for 6 cycles (combination therapy). Following completion of combination therapy, maintenance treatment with farletuzumab 1.25 mg/kg, administer as IV infusion, weekly is given until disease progression. | Drug: Farletuzumab<br>* Farletuzumab IV infusion.<br>* Other names: MORAb-003;Drug: Carboplatin<br>* Carboplatin IV infusion.<br>Drug: Taxane<br>* Taxane (Paclitaxel or Docetaxel) IV infusion.<br>|
| Active Comparator: Farletuzumab (2.5 mg/kg)<br>Participants will receive farletuzumab 2.5 mg/kg administer as an IV infusion weekly, followed by taxane (paclitaxel [175 mg/m^2] or docetaxel [75 mg/m^2]), administer as IV infusion and followed by carboplatin (to maintain AUC 5-6 mg/mL/minute), administer as IV infusion, every three weeks on Day 1 of each 21-day cycle for 6 cycles (combination therapy). Following completion of combination therapy, maintenance treatment with farletuzumab 2.5 mg/kg, administer as IV infusion, weekly is given until disease progression. | Drug: Farletuzumab<br>* Farletuzumab IV infusion.<br>* Other names: MORAb-003;Drug: Carboplatin<br>* Carboplatin IV infusion.<br>Drug: Taxane<br>* Taxane (Paclitaxel or Docetaxel) IV infusion.<br>|
| Placebo Comparator: Placebo<br>Participants will receive farletuzumab-matched placebo (0.9 percent [%] saline) administer as an IV infusion weekly, followed by taxane (paclitaxel [175 mg/m^2] or docetaxel [75 mg/m^2]), administer as IV infusion and followed by carboplatin (to maintain AUC 5-6 mg/mL/minute), administer as IV infusion, every three weeks on Day 1 of each 21-day cycle for 6 cycles (combination therapy). Following completion of combination therapy, maintenance treatment with farletuzumab-matched placebo (0.9% saline), administer as IV infusion, weekly is given until disease progression. | Drug: Carboplatin<br>* Carboplatin IV infusion.<br>Drug: Taxane<br>* Taxane (Paclitaxel or Docetaxel) IV infusion.<br>Drug: Farletuzumab-matched placebo<br>* Farletuzumab-matched placebo IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time (in months) from the date of randomization to the date of the first observation of progression based on the independent radiologic assessment (modified response evaluation criteria in solid tumors [RECIST]), or date of death, whatever the cause. As per RECIST, disease progression was defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. If progression or death was not observed for a participant, the PFS time was censored at the date of the last tumor assessment without evidence of progression before the date of initiation of further antitumor treatment, or the cutoff date (whichever was earlier). | From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (up to 44 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time (in months) from the date of randomization to the date of death, due to any cause. If death was not observed for a participant, the survival time was censored on the last date the participant was known to be alive or the cutoff date, whichever was earlier. | From the date of randomization until date of death from any cause, or study termination by sponsor, whichever came first (up to 48 months) | 
| Cancer Antigen-125 (CA-125) Progression-Free Survival | CA-125 PFS was defined as the time (in months) from the date of randomization until the date of the first observation of progression based on the Rustin criteria, or date of death, whatever the cause. If progression or death was not observed for a participant, the CA-125 PFS time was censored at the date of the last CA-125 assessment without evidence of progression before the date of initiation of further antitumor treatment or the primary analysis cut off date, whichever was earlier. Based on Rustin criteria, progressive disease (PD) was a rise in CA125 since beginning of consolidation or previously normal CA125 that rises to greater than or equal to (>=) 2 multiple (*) ULN with either event documented on two occasions or CA-125 >=2*nadir value with either event documented on two occasions. | From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (up to 44 months) | 
| Progression-Free Survival Based on Gynecologic Cancer InterGroup (GCIG) Criteria | PFS using GCIG criteria was defined as time (in months) from date of randomization until date of first observation of progression based on GCIG criteria, or date of death, whatever the cause. If progression or death was not observed for a participant, GCIG PFS time was censored at later date of last tumor assessment or CA-125 assessment without evidence of progression before date of initiation of further antitumor treatment or the primary analysis cut off date, whichever was earlier. Disease progression per GCIG: Participants with elevated CA-125 pretreatment and normalisation of CA-125 must show evidence of CA-125 >=two times ULN on two occasions at least one week apart or participants with elevated CA-125 pretreatment, which never normalises must show evidence of CA-125 >=two times nadir value on two occasions at least one week apart or participants with CA-125 in normal range pretreatment must show evidence of CA-125 >=two times ULN on two occasions at least one week apart. | From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (up to 44 months) | 
| Percentage of Participants With Length of Second Remission Greater Than First Remission | Length of first remission was defined as a.) the period of time (in months) from the date of completion of previous platinum-based chemotherapy until date of first relapse (that is, first observation of progression). It was assumed that the date of first relapse was the earlier of progression by CA-125 or progression by radiologic assessment, as judged by the investigator using GCIG criteria. b.) the period of time (in months) from the date of completion of previous platinum-based chemotherapy (used prior to study entry) until date of randomization. The length of the second remission was defined as the period of time (in months) from the date of completion of platinum-based chemotherapy until the first observation of progression based on GCIG criteria. Based on GCIG criteria, disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. | From the date of last dose of platinum-based chemotherapy to date of relapse and date of last dose of platinum-based chemotherapy to first observation of progression (up to 48 months) | 
| Percentage of Participants With Objective Response | Objective response was defined as either a confirmed complete response (CR) or confirmed partial response (PR) as assessed by investigator based on response evaluation criteria in solid tumors version 1.1 (RECIST version 1.1). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis less than (<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. | From the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first (up to 48 months) | 
| Duration of Tumor Response | Duration of response was defined as the time (in months) from first documentation of objective response (confirmed CR or PR) to the first documentation of objective tumor progression or death due to any cause. Duration of response was derived only for those participants with objective evidence of confirmed CR or PR. | From the first date of confirmed objective response (CR or PR) to first date of progression or death due to any cause (up to 48 months) | 
| Time to Tumor Response (TTR) | Time to tumor response was defined as the time (in months) from the date of randomization to first documentation of objective tumor response. Time to tumor response was derived for those participants with objective evidence of CR or PR. | From the date of randomization to first documentation of objective response (up to 48 months) | 
| Percentage of Participants With Serologic Response (SR) | SR was defined as either normalization, 75% response, or 50% response using the Rustin criteria. Percentage of participants with 50% SR, 75% SR and SR leading to normalization were reported. A 50% response according to CA-125 was defined as a 50% decrease in serum CA-125 levels, as determined through a series of four CA-125 samples (one baseline sample with an elevated level, the sample that showed a 50% decrease, and a confirmatory sample at the decreased level). A 75% response was established if there had a serial decrease in serum CA-125 levels of 75% over three samples. In both the 50% and 75% response definitions, the final sample was analyzed at least 28 days after the previous sample. | Up to 48 months | 
| Duration of 50% Serologic Response | Duration of SR was defined as the time (in months) from first documentation of response to the first documentation of 50% serologic progression or death due to any cause. For responding participants who did not have serologic progression or did not die and who 1) were either still on study at the time of an analysis, 2) were given antitumor treatment other than study treatment, or 3) were withdrawn from study follow-up before documentation of serologic progression, the duration of SR was censored at the last date the participant was known to be without serologic progression. A 50% response according to CA-125 was defined as a 50% decrease in serum CA-125 levels, as determined through a series of three CA-125 samples (one baseline sample with an elevated level, the sample that showed a 50% decrease, and a confirmatory sample at the decreased level). | From the first date of documentation of response to first documentation of serologic progression or death due to any cause (up to 48 months) | 
| Time to 50% Serologic Response (TSR) | TSR was defined as the time (in months) from the date of randomization to first documentation of 50% SR. A 50% response according to CA-125 was defined as a 50% decrease in serum CA-125 levels, as determined through a series of three CA-125 samples (one baseline sample with an elevated level, the sample that showed a 50% decrease, and a confirmatory sample at the decreased level). | From the date of randomization to first documentation of 50% SR (up to 48 months) | 
| Percentage of Participants With Clinical Benefit | Clinical benefit was defined as a confirmed CR or a confirmed PR, or stable disease (SD) using RECIST 1.0 criteria. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis <10 mm. PR was defined as at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference smallest sum of longest dimensions since treatment started associated to non-progressive disease response for non target lesions. | Up to 48 months | 
| Cmax: Maximum Observed Plasma Concentration of Total Carboplatin and Total Paclitaxel |  | Cycle 2 Week 1 Day 1: 0-45 hours post-dose (cycle length=21 days) | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Total Carboplatin and Total Paclitaxel |  | Cycle 2 Week 1 Day 1: 0-45 hours post-dose (cycle length=21 days) | 
| AUC (0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Total Carboplatin and Total Paclitaxel |  | Cycle 2 Week 1 Day 1: 0-45 hours post-dose (cycle length=21 days) | 
| T1/2: Terminal Half-life of Total Carboplatin and Total Paclitaxel |  | Cycle 2 Week 1 Day 1: 0-45 hours post-dose (cycle length=21 days) | 
| CL: Clearance of Total Carboplatin and Total Paclitaxel |  | Cycle 2 Week 1 Day 1: 0-45 hours post-dose (cycle length=21 days) | 
| Vd: Volume of Distribution of Total Carboplatin and Total Paclitaxel |  | Cycle 2 Week 1 Day 1: 0-45 hours post-dose (cycle length=21 days) | 
| Mean Functional Assessment of Cancer Therapy-Ovarian Treatment Outcome Index (FACT-O TOI) Scores | Participant-reported Quality of Life (QoL) was measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O), version 4 and reported in the Treatment Outcome Index (TOI) format. TOI is a 26-item subset of the FACT-O questionnaire composed of the raw sum of the physical well-being subscale (7 items), the functional well-being subscale (7 items), and the ovarian cancer subscale (12 items). Each item was scored on a scale of 0 (not at all) to 4 (very much). Some items were reversed scored. Scores from each subsection were summed into one composite score, termed the FACT-O TOI score which ranged from 0 to 104 and a higher score reflected better QoL. As per planned analysis, farletuzumab treatment groups 1.25 mg/kg and 2.5 mg/kg were pooled for the QoL assessment. | Cycle 3, Cycle 6, Cycle 12 (each cycle length=21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian cancer, relapsed ovarian cancer, Platinum-sensitive Ovarian Cancer