A Randomized Phase 3, Double-Blind Study of Chemotherapy With or Without Pembrolizumab Followed by Maintenance With Olaparib or Placebo for the First-Line Treatment of BRCA non-mutated Advanced Epithelial Ovarian Cancer (EOC) (KEYLYNK-001 / ENGOT-ov43 / GOG-3036)
- Trial ID
- 2022-502124-52-00
- Protocol
- MK-7339-001
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival (PFS)** as assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This is clinically relevant as PFS is a critical endpoint in evaluating the efficacy of treatments in **advanced epithelial ovarian cancer**, providing insights into the duration a patient lives without disease progression.
Secondary objectives include:
- To compare the overall survival (OS).
- To compare the PFS as assessed by blinded independent central review according to RECIST 1.1 in participants with PD-L1 positive tumors (CPS ≥10) and in all participants.
- To compare the PFS after second-line treatment as determined by the investigator according to the local standard of clinical practice (PFS2) following discontinuation of study treatment administration in participants with PD-L1 positive tumors (CPS ≥10) and in all participants.
- To evaluate the safety and tolerability of pembrolizumab administered with chemotherapy and olaparib maintenance.
- To compare the mean change from baseline of Global Health Status/Quality-of-Life (GHS/QoL) score using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and abdominal and gastrointestinal (abdominal/GI) symptoms using the EORTC Ovarian Cancer-Specific Quality-of-Life Questionnaire (QLQ-OV28) abdominal/GI symptom scale.
- To compare time to deterioration (TTD) of GHS/QoL score using EORTC QLQ-C30 and abdominal/GI symptoms using EORTC QLQ-OV28.
- To compare the time to first subsequent anticancer treatment (TFST), the time to second subsequent anticancer treatment (TSST), and the time to discontinuation of study treatment or death (TDT).
- To compare the rate of locally determined pathological complete response (pCR) of pembrolizumab in combination with carboplatin/paclitaxel versus carboplatin/paclitaxel alone when administered as neoadjuvant therapy.
Participants
The clinical trial involves a total of **838 participants** diagnosed with **advanced epithelial ovarian cancer**. The study population is exclusively female, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific inclusion criteria, such as having histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. All participants have either completed or are eligible for primary debulking surgery and are candidates for carboplatin and paclitaxel chemotherapy. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are in relatively good health despite their condition. Lifestyle considerations include the requirement for women of childbearing potential to use highly effective contraception or abstain from heterosexual intercourse during the treatment period. The trial does not include male participants, and it involves a vulnerable population, highlighting the need for careful ethical considerations in the study design and execution.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of chemotherapy with or without **pembrolizumab**, followed by maintenance therapy with **olaparib** or placebo, in patients with **advanced epithelial ovarian cancer**. The primary objective is to compare progression-free survival as assessed by the investigator according to RECIST 1.1 criteria. The trial is expected to run from December 18, 2018, to May 30, 2025, with participants involved for a maximum treatment period of 105 weeks, depending on the treatment arm and individual response.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed FIGO Stage III or IV ovarian cancer and adequate organ function. Following successful screening, participants will be randomized to receive either the investigational treatment or placebo. The treatment phase includes administration of **carboplatin** and **paclitaxel** chemotherapy, with or without pembrolizumab, followed by maintenance therapy with olaparib or placebo. Study visits will occur regularly to monitor safety, efficacy, and adherence to the protocol.
Follow-up visits will be scheduled to assess progression-free survival and overall survival, as well as to monitor for adverse events and quality of life changes using the EORTC QLQ-C30 and QLQ-OV28 questionnaires. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be closely monitored throughout the study to ensure compliance with the protocol and to address any safety concerns promptly.
Treatment
The clinical trial involves several treatments, including both experimental and non-experimental medications. **Paclitaxel** is administered as an intravenous infusion with a pharmaceutical form designated as PHF00016MIG. The maximum daily dose is 175 mg/m², with a total maximum dose of 1050 mg/m² over a treatment period of 18 weeks. This chemical substance is used as a standard chemotherapy agent in the study.
**Olaparib** is provided in the form of a film-coated tablet, with a maximum daily dose of 300 mg and a total maximum dose of 219,000 mg over a 24-week period. It is administered orally and serves as a test medication in the trial. The sponsor product code for Olaparib is MK-7339, and it is produced by Merck & Co. Inc.
**Anhydrous Docetaxel** is another chemotherapy agent used in the study, administered via intravenous infusion. It has a pharmaceutical form of PHF00230MIG, with a maximum daily dose of 75 mg/m² and a total maximum dose of 450 mg/m² over 18 weeks. This chemical substance is used as a comparator treatment.
**Carboplatin** is administered as an intravenous infusion with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 900 mg, with a total maximum dose of 5400 mg over an 18-week period. It is used as a standard chemotherapy agent in the trial.
The study also includes a **placebo** to Olaparib, provided in tablet form, and a placebo to pembrolizumab, administered as normal saline/dextrose. These placebos are used to maintain the double-blind nature of the trial.
**Pembrolizumab**, marketed as Keytruda, is administered as a concentrate for solution for infusion. The maximum daily dose is 200 mg, with a total maximum dose of 7000 mg over a 105-week period. It is a biologic agent used as a test medication in the study, with the sponsor product code MK-3475.
**Bevacizumab** is administered via intravenous infusion, with a maximum daily dose of 15 mg/kg and a total maximum dose of 90 mg/kg over 18 weeks. It is a biologic agent used as a comparator treatment in the trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as evaluated by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This assessment will be conducted in participants with Programmed Death-Ligand 1 (PD-L1)-positive tumors, as well as in all participants. Secondary endpoints include Overall Survival (OS) in all participants and specifically in those with PD-L1-positive tumors. Additionally, PFS will be assessed by a Blinded Independent Central Review (BICR) in both PD-L1-positive participants and the overall participant group.
Further secondary endpoints involve the evaluation of PFS after second-line treatment following discontinuation of study treatment, the number of participants experiencing adverse events, and those discontinuing treatment due to adverse events. Quality of life measures will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the EORTC Quality of Life Questionnaire-Ovarian Cancer (QLQ-OV28), focusing on changes from baseline in global health status and abdominal/gastrointestinal symptoms. Time to deterioration of these scores will also be measured. Additional endpoints include Time to First Subsequent Anti-cancer Treatment (TFST), Time to Second Subsequent Anti-cancer Treatment (TSST), Time to Discontinuation of Study Treatment or Death (TDT), and Pathological Complete Response (pCR) Rate.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) Stage III or Stage IV EOC (high-grade predominantly serous, endometrioid (any grade), carcinosarcoma, mixed mullerian with high-grade serous component, clear cell, or low-grade serous OC), primary peritoneal cancer, or fallopian tube cancer
- Has just completed primary debulking surgery or is eligible for primary debulking surgery or is a potential candidate for interval debulking surgery
- Is a candidate for carboplatin and paclitaxel chemotherapy, to be administered in the adjuvant or neoadjuvant setting
- Candidates for neoadjuvant chemotherapy, has a cancer antigen 125 (CA-125) (kilounits/L):carcinoembryonic antigen (CEA; ng/mL) ratio greater than or equal to 25
- Is able to provide a newly obtained core or excisional biopsy of a tumor lesion for prospective testing of BRCA1/2 and Programmed Cell Death-Ligand 1 (PD-L1) tumor markers status prior to randomization
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to initiating chemotherapy in the lead-in period and within 3 days prior to Day 1 of Cycle 1
- Female participants are not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) OR b.) Is a WOCBP and using a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the Treatment Period and for at least 120 days following the last dose of pembrolizumab (or pembrolizumab placebo) and bevacizumab (if administered), at least 180 days following the last dose of olaparib (or olaparib placebo), and at least 210 days following the last dose of chemotherapy and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study treatment. A WOCBP must have a negative highly sensitive pregnancy test within either 24 hours (urine) or 72 hours (serum) before the first dose of study treatment. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Has adequate organ function
Exclusion Criteria
- Has mucinous, germ cell, or borderline tumor of the ovary
- Has a known or suspected deleterious mutation (germline or somatic) in either BRCA1 or BRCA2
- Has a history of non-infectious pneumonitis that required treatment with steroids or currently has pneumonitis
- Has either myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
- Has a known additional malignancy that is progressing or has required active treatment in the last 3 years Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. ductal carcinoma in situ, cervical carcinoma in situ) that has undergone potentially curative therapy are not excluded.
- Has ongoing Grade 3 or Grade 4 toxicity, excluding alopecia, following chemotherapy administered during the lead-in period
- Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with brain metastases may participate provided they were previously treated (except with chemotherapy) and are radiologically stable, clinically stable, and no steroids were used for the management of symptoms related to brain metastases within 14 days prior to randomization. Stable brain metastases should be established prior to the first dose of study medication lead-in chemotherapy
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing >10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
- Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
- Has a known history of active tuberculosis (TB; Bacillus Tuberculosis)
- Has an active infection requiring systemic therapy
- Has received colony-stimulating factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 4 weeks prior to receiving chemotherapy during the lead-in period
- Is considered to be of poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection
- Has had surgery to treat borderline tumors, early-stage EOC, or early-stage fallopian tube cancer <6 months prior to screening
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Testing for hepatitis B or hepatitis C is required at screening only if mandated by local health authority. Note: Participants with a history of hepatitis B but who are HBsAg negative are eligible for the study
- Is either unable to swallow orally administered medication or has a gastrointestinal (GI) disorder affecting absorption (e.g. gastrectomy, partial bowel obstruction, malabsorption)
- Has uncontrolled hypertension
- Has current, clinically relevant bowel obstruction (including sub-occlusive disease), abdominal fistula or GI perforation, related to underlying EOC (for participants receiving bevacizumab)
- Has a history of hemorrhage, hemoptysis or active GI bleeding within 6 months prior to randomization (for participants receiving bevacizumab)
- Is a WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of chemotherapy in the lead-in period and within 72 hours prior to Day 1 of Cycle 1, is pregnant or breastfeeding, or is expecting to conceive children within the projected duration of the study, starting with screening through 120 days following the last dose of pembrolizumab (or pembrolizumab placebo) and bevacizumab (if administered), at least 180 days following the last dose of olaparib (or olaparib placebo), and at least 210 days following the last dose of chemotherapy
- Has received prior treatment for any stage of OC, including radiation or systemic anti-cancer therapy (e.g. chemotherapy, hormonal therapy, immunotherapy, investigational therapy)
- Has received prior therapy with an anti-Programmed Cell Death-1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T lymphocyte antigen-4 [CTLA-4], OX 40, CD137)
- Has received prior therapy with either olaparib or any other poly(adenosine-ribose) polymerase (PARP) inhibitor
- Has intraperitoneal chemotherapy planned or has been administered as first-line therapy
- Has received a live vaccine within 30 days prior to the first dose of study treatment on Day 1 of Cycle 1
- Has severe hypersensitivity (≥Grade 3) to pembrolizumab, olaparib, carboplatin, paclitaxel, or bevacizumab (if using) and/or any of their excipients
- Is currently receiving either strong (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
- Is currently receiving either strong (e.g. phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, and St John's Wort) or moderate (e.g. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
- Is currently participating or has participated in a study of an investigational agent or has used an investigational device within 4 weeks (28 days) of starting chemotherapy in the Lead-in Period
- Has resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions or participant has congenital long QT syndrome
- Has had an allogenic tissue/solid organ transplant, has received previous allogenic bone-marrow transplant, or has received double umbilical cord transplantation
- Either has had major surgery within 3 weeks of randomization or has not recovered from any effects of any major surgery
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Dec 2018 | 111 |
 Czechia | Not Recruiting | 18 Dec 2018 | 50 |
 France | Not Recruiting | 18 Dec 2018 | 37 |
 Germany | Not Recruiting | 18 Dec 2018 | 44 |
 Hungary | Not Recruiting | 18 Dec 2018 | 28 |
 Italy | Not Recruiting | 18 Dec 2018 | 120 |
 Poland | Not Recruiting | 18 Dec 2018 | 59 |
 Spain | Not Recruiting | 18 Dec 2018 | 80 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CARBOPLATIN | Other | PHF00230MIG | INTRAVENOUS INFUSION | 900 | 18 | SCP28192792 |
DOCETAXEL | Other | PHF00230MIG | INTRAVENOUS INFUSION | 75 | 18 | SCP725130 |
Placebo to pembrolizumabnormal saline/dextrose | Placebo | N/A | — | — | — | N/A |
Olaparib | Test | FILM-COATED TABLET | ORAL | 300 | 24 | PRD9414228 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 200 | 105 | PRD4323105 |
PACLITAXEL | Other | PHF00016MIG | INTRAVENIOUS INFUSION | 175 | 18 | SCP247399 |
Placebo to Olaparib - Tablet | Placebo | N/A | — | — | — | N/A |
- | Other | - | INTRAVENIOUS INFUSION | 15 | 18 | SCP27276 |
Olaparib | Test | FILM-COATED TABLET | ORAL | 300 | 24 | PRD9414227 |