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

Phase 3

Active, not recruiting

• Conditions: Ovarian Cancer; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms
• Interventions: Biological: Pembrolizumab; Drug: Paclitaxel; Other: Placebo for pembrolizumab; Drug: Bevacizumab; Drug: Docetaxel

• Registration Number: NCT05116189
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-10-28
• Study First Submitted QC: 2021-10-28
• Study First Posted: 2021-11-10
• Study Start: 2021-12-13
• Primary Completion: 2025-03-05
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-10
• Last Update Posted: 2025-07-14
• Study Completion: 2028-10-25

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Female
• Target Recruitment: 643

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pembrolizumab + paclitaxel ± bevacizumab	Pembrolizumab	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.
Placebo + paclitaxel ± bevacizumab	Placebo for pembrolizumab	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.
Pembrolizumab + paclitaxel ± bevacizumab	Paclitaxel	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.
Pembrolizumab + paclitaxel ± bevacizumab	Bevacizumab	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.
Pembrolizumab + paclitaxel ± bevacizumab	Docetaxel	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.
Placebo + paclitaxel ± bevacizumab	Paclitaxel	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.
Placebo + paclitaxel ± bevacizumab	Bevacizumab	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.
Placebo + paclitaxel ± bevacizumab	Docetaxel	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by Investigator	Up to ~38 months	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Up to ~64 months	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.
PFS per RECIST 1.1 by Blinded Independent Central Review (BICR)	Up to ~38 months	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.
Number of Participants who Experience an Adverse Event (AE)	Up to ~64 months	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.
Number of Participants who Discontinue Study Treatment due to an AE	Up to ~64 months	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.
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)	Baseline and up to ~64 months	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.
Time to Deterioration (TTD) in the GHS/Qol Score (Items 29 and 30) Using the EORTC QLQ-C30	Up to ~64 months	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.
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	Baseline and up to ~64 months	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.
TTD in the Abdominal and GI Symptoms Score (Items 31 to 36) Using the EORTC QLQ-OV28 Abdominal/GI Symptom Scale	Up to ~64 months	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.

Trial Locations

Locations (187)

HonorHealth ( Site 0041); 🇺🇸 Phoenix, Arizona, United States

Marin Cancer Care ( Site 0055); 🇺🇸 Greenbrae, California, United States

Pacific Cancer Care ( Site 0028); 🇺🇸 Monterey, California, United States

Eisenhower Medical Center ( Site 0067); 🇺🇸 Rancho Mirage, California, United States

Yale-New Haven Hospital-Smilow Cancer Hospital at Yale-New Haven ( Site 0004); 🇺🇸 New Haven, Connecticut, United States

University of Florida College of Medicine-UF Health Cancer Center/Clinical Trials Office ( Site 0054; 🇺🇸 Gainesville, Florida, United States

Sarasota Memorial Hospital ( Site 0018); 🇺🇸 Sarasota, Florida, United States

Moffitt Cancer Center ( Site 0033); 🇺🇸 Tampa, Florida, United States

Northwest Georgia Oncology Centers, a Service of Wellstar Cobb Hospital-Research ( Site 0005); 🇺🇸 Marietta, Georgia, United States

Advocate Medical Group-Oncology ( Site 0049); 🇺🇸 Park Ridge, Illinois, United States

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