A Study to Assess the Efficacy and Safety of Farletuzumab (MORAb 003) in Combination With Carboplatin Plus Paclitaxel or Carboplatin Plus Pegylated Liposomal Doxorubicin (PLD) in Participants With Low CA125 Platinum-sensitive Ovarian Cancer

Study Overview
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Brief Summary
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MORAb-003-011 is a global, multicenter, double-blind, randomized placebo-controlled study to assess the safety and efficacy of farletuzumab in combination with standard chemotherapy in subjects with low cancer antigen 125 (CA125) platinum-sensitive ovarian cancer in first relapse.

Detailed Description
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Participants will be enrolled into 1 of 2 chemotherapy treatment arms at the investigator's discretion: carboplatin plus paclitaxel or carboplatin plus Pegylated Liposomal Doxorubicin (PLD), and then randomized in a 2:1 ratio to receive weekly farletuzumab 5 mg/kg or placebo (ie, Test Article). All participants will receive a loading dose for the first 2 weeks of 10 mg/kg Test Article (farletuzumab or placebo). Participants will be stratified at randomization by individual chemotherapy treatment regimen (targeted 1:1 ratio) and platinum-free interval following first-line therapy (6 to 12 months vs greater than 12 to 36 months).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Efficacy and Safety of Farletuzumab (MORAb 003) in Combination With Carboplatin Plus Paclitaxel or Carboplatin Plus Pegylated Liposomal Doxorubicin (PLD) in Subjects With Low CA125 Platinum-Sensitive Ovarian Cancer

Conditions
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Platinum-Sensitive Ovarian Cancer in First Relapse

Intervention / Treatment
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* Drug: Farletuzumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female subjects who are at least 18 years of age at the time of informed consent CA125 less than or equal to 3 x upper limit of normal (ULN) [105 units per millilitre (U/mL)] confirmed within 2 weeks of randomization using a centralized laboratory assay A histologically confirmed diagnosis of high-grade serous epithelial ovarian cancer including primary peritoneal and fallopian tube malignancies; all other histologies, including mixed histology, are excluded Have been treated with debulking surgery and a first-line platinum-based chemotherapy regimen Maintenance therapy during the first platinum-free interval is allowed; however, the last dose must have been at least 21 days prior to Randomization. Must be in a first relapse and have evaluable disease by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan, according to RECIST 1.1 (subjects with measurable disease per RECIST 1.1 or radiographically visible and evaluable disease). Subjects with only ascites or pleural effusion are excluded. Must have relapsed radiographically between 6 months and 36 months of completion of first-line platinum chemotherapy Must be a candidate for treatment with either carboplatin plus paclitaxel or carboplatin plus PLD with no medical contraindications present as outlined in the product labels for the selected regimen to be used in this study Have a life expectancy of at least 6 months, as estimated by the investigator Other significant medical conditions must be well-controlled and stable in the opinion of the investigator for at least 30 days prior to Randomization Have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Subjects being enrolled to receive paclitaxel plus carboplatin treatment must have neuropathic function (sensory and motor less than or equal to Grade 2 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (2010) Laboratory results within the 2 weeks prior to Randomization must be as follows: Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L Platelet count greater than or equal to 100 x 10^9/L Hemoglobin greater than or equal to 9 g/dL Creatinine less than 1.5 x ULN (CTCAE Grade 1) Bilirubin less than 1.5 x ULN (CTCAE Grade 1) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) less than 3 x ULN Alkaline Phosphatase less than 2.5 x ULN (CTCAE Grade 1) Baseline albumin greater than or equal to Lower Limit of Normal Subjects of childbearing potential must be surgically sterile or consent to use a medically acceptable method of contraception throughout the study period. All females will be considered to be of childbearing potential unless they are postmenopausal (eg, amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). If a patient of childbearing potential is neither surgically sterile nor postmenopausal, a highly-effective contraceptive method (ie, a method that can achieve a failure rate of less than 1 percent (%) per year when used consistently and correctly) must start either before or at Screening and continue throughout the entire study period and for 6 months after the last dose of Test Article is administered. Pregnant and/or lactating females are excluded Exclusion Criteria: Known central nervous system (CNS) tumor involvement Evidence of other active invasive malignancy requiring treatment other than surgery in the past 3 years Clinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4 angina, not well controlled by medication, or myocardial infarction within 6 months) Electrocardiogram (ECG) demonstrating clinically significant arrhythmias that are not adequately medically managed (Note: subjects with chronic atrial arrhythmia, ie, atrial fibrillation or paroxysmal supraventricular tachycardia [SVT], are eligible) Active serious systemic disease, including active bacterial or fungal infection Active viral hepatitis or active human immunodeficiency virus (HIV) infection. Asymptomatic positive serology is not exclusionary. Other concurrent immunotherapy (eg, immunosuppressants or chronic use of systemic corticosteroids, with the exception that low-dose corticosteroids [50 mg/day prednisone or equivalent corticosteroid] are allowed; these should be discussed with the Medical Monitor) Known allergic reaction to a prior monoclonal antibody therapy or have any documented Anti-Drug Antibody (ADA) response; additionally known allergic reaction to the concomitant chemotherapies selected by the investigator for planned treatment in this study unless desensitization is planned Previous treatment with farletuzumab or other folate receptor targeting agents Previous treatment with cancer vaccine therapy For subjects being enrolled to receive PLD plus carboplatin, prior treatment with anthracyclines or anthracenodiones Breast-feeding, pregnant, or likely to become pregnant during the study Any medical or other condition that, in the opinion of the investigator, would preclude the subject's participation in a clinical study including medical contraindications as outlined in the product labels for the chemotherapies selected by the investigator for planned treatment in this study Patients who have had secondary debulking surgery or any second line therapy Currently enrolled in another clinical study or used any investigational drug or device within 30 days (or 5 x half-life for investigational drugs where the half-life is known) preceding informed consent

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Farletuzumab<br>All participants will receive a loading dose for the first 2 weeks of 10 milligram per kilogram (mg/kg) farletuzumab, followed by 5 mg/kg weekly farletuzumab administered intravenously (IV). | Drug: Farletuzumab<br>* Farletuzumab will be administered intravenously (IV) weekly<br>|
| Placebo Comparator: Placebo<br>All subjects will receive placebo weekly, administered intravenously (IV). | Drug: Placebo<br>* Placebo will be administered intravenously (IV) weekly<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 of a participant to the date of first observation of progression or date of death, whatever the cause. PFS was assessed based on the investigators' assessments utilizing Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Disease progression (PD) was defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. | From the date of randomization to the date of first documentation of PD, or date of death, whichever occurs first up to approximately 5 years 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the date of randomization until the date of death. Participants were censored at the date of last known to be alive. OS was analyzed using Kaplan-Meier method. | From the date of randomization until the date of death (up to approximately 5 years 5 months) | 
| Number of Participants With Best Overall Response (BOR) | BOR was defined as the best response of complete response (CR) or partial response (PR) or stable disease (SD) for greater than or equal to(>=)6 months recorded from the start of the treatment until PD or death, whichever occurred first based on investigator assessment per RECIST v1.1. CR:disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis less than(<)10 mm. PR:at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD. PD was defined as at least 20% increase (including an absolute increase of at least 5mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From first dose of study drug (Baseline) up to approximately 5 years 5 months | 
| Time to Tumor Response (TTR) | TTR was defined as the time (in months) from the date of randomization to the date of first observation of response (PR or CR) (whichever status was recorded first). TTR was assessed based on investigator assessment utilizing RECIST 1.1. CR: disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. | From the date of randomization until date of first observation of response (CR or PR) up to approximately 5 years 5 months | 
| Duration of Response (DOR) | DOR was defined as the time (in months) from the date of first observation of response (PR or CR) to the date of the first observation of progression based on the investigator's assessment utilizing RECIST 1.1, or date of death, whatever the cause. CR: disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30 % decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From date of the first observation of CR or PR until the date of first observation of progression or date of death up to approximately 5 years 5 months | 
| Percentage of Participants Achieving Each Second Platinum-Free Interval Stratified by First Platinum-Free Interval | Percentage of participants achieving each second platinum-free interval (<6 months, 6-12 months, greater than [>] 12-36 months, and >36 months) stratified by first platinum-free interval (6 to 12 months and >12 to 36 months) was reported. First platinum-free interval was defined as the date of completion of previous platinum-based chemotherapy until the date of first relapse (that is, first observation of progression). The date of first relapse was the progression date. Second platinum-free interval was defined as the date of completion of platinum-based chemotherapy (last dosing date) during the study until the date of progression or death (or censoring, if applicable). | From the date of randomization to the date of first relapse (or first observation of progression/death) up to approximately 5 year 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Cancer in in first relapse, Platinum-Sensitive