Pembrolizumab/Placebo Plus Paclitaxel With or Without Bevacizumab for Platinum-resistant Recurrent Ovarian Cancer (MK-3475-B96/KEYNOTE-B96/ENGOT-ov65)

Study Overview
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Brief Summary
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The primary objective is to compare pembrolizumab plus paclitaxel with or without bevacizumab to placebo plus paclitaxel with or without bevacizumab, with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the investigator. The hypotheses are that pembrolizumab plus paclitaxel with or without bevacizumab is superior to placebo plus paclitaxel with or without bevacizumab, with respect to PFS per RECIST 1.1 as assessed by the investigator for participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score [CPS] ≥1) and that pembrolizumab plus paclitaxel with or without bevacizumab is superior to placebo plus paclitaxel with or without bevacizumab, with respect to PFS per RECIST 1.1 as assessed by the investigator for all participants.

Official Title
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A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Versus Placebo in Combination With Paclitaxel With or Without Bevacizumab for the Treatment of Platinum-resistant Recurrent Ovarian Cancer (KEYNOTE-B96/ENGOT-ov65)

Conditions
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Ovarian Cancer, Carcinoma, Ovarian Epithelial, Fallopian Tube Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Paclitaxel
* Drug: Bevacizumab
* Other: Placebo for pembrolizumab
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Has received 1 or 2 prior lines of systemic therapy for ovarian cancer (OC), including at least 1 prior platinum-based therapy. Participants may have received a prior poly (ADP-ribose) polymerase inhibitor (PARPi), anti-PD-1/anti-PD-L1 therapy, bevacizumab, or hormonal therapy; these will not be considered a separate line of therapy. Any chemotherapy regimen change due to toxicity in the absence of disease progression will be considered part of the same line of therapy. Has provided documented informed consent for the study. Has radiographic evidence of disease progression within 6 months (180 days) after the last dose of platinum-based chemotherapy for OC (i.e., platinum-resistant disease). Is a candidate for paclitaxel chemotherapy (and bevacizumab, if using). Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 3 days before randomization. For a female participant, she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and uses a contraceptive method that is highly effective (with a failure rate of <1% per year). Has radiographically evaluable disease, either measurable or nonmeasurable per RECIST 1.1, as assessed by the local site investigator. Archival tumor tissue sample or newly obtained core or incisional/excisional biopsy of a tumor lesion not previously irradiated has been provided. Have adequate organ function. Exclusion Criteria: Has nonepithelial cancers, borderline tumors, mucinous, seromucinous that is predominantly mucinous, malignant Brenner's tumor and undifferentiated carcinoma. Has primary platinum-refractory disease, defined as disease that has progressed per radiographic imaging while receiving or within 28 days of the last dose of first-line platinum-based therapy. Has prior disease progression on weekly paclitaxel alone. Has received >2 prior lines of systemic therapy for OC. Has received prior systemic anticancer therapy including investigational agents or maintenance therapy (including bevacizumab maintenance therapy), within 4 weeks before randomization. Has received prior radiation therapy within 2 weeks of start of study intervention. Has not recovered adequately from surgery and/or any complications from the surgery. Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor,[GM-CSF] or recombinant erythropoietin) within 4 weeks before randomization. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Has received investigational agent or has used an investigational device within 4 weeks prior to study intervention. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, paclitaxel, or bevacizumab (if using) and/or any of their excipients. Has an active autoimmune disease that has required systemic treatment in the past 2 years. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Has an active infection requiring systemic therapy. Has a known history of human immunodeficiency virus (HIV) infection. Has a known history of Hepatitis B or known active Hepatitis C virus infection. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Participant, in the judgement of the investigator, is unlikely to comply with the study procedures, restrictions, and requirements of the study. Has had an allogenic tissue/solid organ transplant. For bevacizumab treatment Has uncontrolled hypertension. Has current, clinically relevant bowel obstruction including related to underlying epithelial OC, abdominal fistula or gastrointestinal perforation, intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic exam. Has a history of thrombotic disorders, hemorrhage, hemoptysis, or active gastrointestinal bleeding within 6 months before randomization.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + paclitaxel ± bevacizumab<br>Participants receive pembrolizumab 400 mg via intravenous (IV) infusion for eighteen 6-week cycles (approximately 2 years) PLUS paclitaxel 80 mg/m^2 via IV infusion on Days 1, 8, and 15 of each 3-week cycle until intolerance or disease progression. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m^2 every 3 weeks [Q3W]) after Sponsor consultation. Participants may also receive bevacizumab 10 mg/kg via IV infusion of each 2-week cycle until intolerance, disease progression, or at the Investigator's discretion. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Bevacizumab<br>* IV infusion<br>* Other names: AVASTIN®, Zirabev;Drug: Docetaxel<br>* IV infusion<br>* Other names: TAXOTERE®;|
| Placebo Comparator: Placebo + paclitaxel ± bevacizumab<br>Participants receive placebo via IV infusion for eighteen 6-week cycles (approximately 2 years) PLUS paclitaxel 80 mg/m^2 via IV infusion on Days 1, 8, and 15 of each 3-week cycle until intolerance or disease progression. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m^2 every 3 weeks [Q3W]) after Sponsor consultation. Participants may also receive bevacizumab 10 mg/kg via IV infusion of each 2-week cycle until intolerance, disease progression, or at the Investigator's discretion. | Drug: Paclitaxel<br>* IV infusion<br>* Other names: TAXOL®;Drug: Bevacizumab<br>* IV infusion<br>* Other names: AVASTIN®, Zirabev;Other: Placebo for pembrolizumab<br>* IV infusion<br>* Other names: normal saline or dextrose;Drug: Docetaxel<br>* IV infusion<br>* Other names: TAXOTERE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by Investigator | PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on Investigator assessment or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by the Investigator will be presented. | Up to  38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of randomization to death due to any cause. The OS will be reported for all participants. | Up to  64 months | 
| PFS per RECIST 1.1 by Blinded Independent Central Review (BICR) | PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review assessment or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by blinded independent central review will be presented. | Up to  38 months | 
| Number of Participants who Experience an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be reported. | Up to  64 months | 
| Number of Participants who Discontinue Study Treatment due to an AE | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be reported. | Up to  64 months | 
| Change From Baseline in Global Health Status/Quality of Life (GHS/Qol) Score (Items 29 and 30) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score will be presented. | Baseline and up to  64 months | 
| Time to Deterioration (TTD) in the GHS/Qol Score (Items 29 and 30) Using the EORTC QLQ-C30 | TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in GHS (EORTC QLQ-C30 Items 29 and 30) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in GHS score, will be presented. A longer TTD indicates a better outcome. | Up to  64 months | 
| Change From Baseline in the Abdominal and Gastrointestinal (GI) Symptoms Score (Items 31 to 36) Using the EORTC Quality of Life Questionnaire-Ovarian Cancer (QLQ-OV28) Abdominal/GI Symptom Scale | The EORTC QLQ-OV28 is an abdominal and gastrointestinal questionnaire (items 31-36). Participant responses to the question Did you have abdominal pain ? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in abdominal and gastrointestinal symptoms (EORTC QLQ-LC28 Items 31-36) score will be presented. A lower score indicates a better outcome. | Baseline and up to  64 months | 
| TTD in the Abdominal and GI Symptoms Score (Items 31 to 36) Using the EORTC QLQ-OV28 Abdominal/GI Symptom Scale | TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in GHS (EORTC QLQ-C28 Items 31-36) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in GHS score, will be presented. A longer TTD indicates a better outcome. | Up to  64 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)