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Study of Chemotherapy With Pembrolizumab (MK-3475) Followed by Maintenance With Olaparib (MK-7339) for the First-Line Treatment of Women With BRCA Non-mutated Advanced Epithelial Ovarian Cancer (EOC) (MK-7339-001/KEYLYNK-001/ENGOT-ov43/GOG-3036)

NCT03740165

Description:

The purpose of this study is to assess the efficacy and safety of treatment with carboplatin/paclitaxel* PLUS pembrolizumab (MK-3475) and maintenance olaparib (MK-7339) in women with epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal cancer. The primary study hypotheses are that the combination of pembrolizumab plus carboplatin/paclitaxel* followed by continued pembrolizumab and maintenance olaparib is superior to carboplatin/paclitaxel alone with respect to Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and/or Overall Survival (OS), and that the combination of pembrolizumab plus carboplatin/paclitaxel followed by continued pembrolizumab is superior to carboplatin/paclitaxel alone with respect to PFS per RECIST 1.1 and/or OS.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Chemotherapy With Pembrolizumab (MK-3475) Followed by Maintenance With Olaparib (MK-7339) for the First-Line Treatment of Women With BRCA Non-mutated Advanced Epithelial Ovarian Cancer (EOC) (MK-7339-001/KEYLYNK-001/ENGOT-ov43/GOG-3036)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 7339-001
  • SECONDARY ID: 2018-001973-25
  • SECONDARY ID: ENGOT-ov43
  • SECONDARY ID: MK-7339-001
  • SECONDARY ID: KEYLYNK-001
  • SECONDARY ID: 194619
  • SECONDARY ID: GOG-3036
  • NCT ID: NCT03740165

Conditions

  • Ovarian Cancer
  • Fallopian Tube Cancer
  • Peritoneal Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab+Olaparib
Placebo for pembrolizumabnormal saline or dextrosePlacebo for Pembrolizumab+Placebo for Olaparib
CarboplatinPARAPLATIN®Pembrolizumab+Olaparib
PaclitaxelTAXOL®Pembrolizumab+Olaparib
OlaparibMK-7339, LYNPARZA®Pembrolizumab+Olaparib
Placebo for olaparibPembrolizumab+Placebo for Olaparib
BevacizumabAVASTIN®Pembrolizumab+Olaparib
DocetaxelPembrolizumab+Olaparib

Purpose

The purpose of this study is to assess the efficacy and safety of treatment with carboplatin/paclitaxel* PLUS pembrolizumab (MK-3475) and maintenance olaparib (MK-7339) in women with epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal cancer. The primary study hypotheses are that the combination of pembrolizumab plus carboplatin/paclitaxel* followed by continued pembrolizumab and maintenance olaparib is superior to carboplatin/paclitaxel alone with respect to Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and/or Overall Survival (OS), and that the combination of pembrolizumab plus carboplatin/paclitaxel followed by continued pembrolizumab is superior to carboplatin/paclitaxel alone with respect to PFS per RECIST 1.1 and/or OS.

Detailed Description

      Following a lead-in period during which all participants receive a single 3-week cycle of
      carboplatin/paclitaxel*, participants will be randomly assigned in to one of three treatment
      arms:

        -  Pembrolizumab+Olaparib,

        -  Pembrolizumab+Placebo for Olaparib

        -  Placebo for Pembrolizumab+Placebo for Olaparib

             -  At Investigator's discretion and prior to participant randomization, one of the
                following carboplatin/paclitaxel regimens is to be selected:

                  1. up to 5 cycles of carboplatin Area Under the Curve (AUC)5 or AUC6 AND
                     paclitaxel 175 mg/m^2 on Day 1 of each 3-week cycle

                  2. up to 5 cycles of carboplatin AUC5 or AUC6 on Day 1 of each 3-week cycle AND
                     paclitaxel 80 mg/m^2 on Days 1, 8 and 15 of each 3-week cycle; or

                  3. up to 5 cycles of carboplatin AUC2 or AUC2.7 AND paclitaxel 60 mg/m^2 on Days
                     1, 8 and 15 of each 3-week cycle.

      Docetaxel may be considered for participants who experience either a severe hypersensitivity
      reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after
      consultation with the Sponsor. The recommended dose as determined by the Scottish
      Gynaecological Cancer Trials Group is Docetaxel 75 mg/m^2 Q3W plus carboplatin AUC 5 Q3W.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab+OlaparibExperimentalParticipants receive carboplatin/paclitaxel via intravenous (IV) infusion for five 3-week cycles PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles PLUS olaparib 300 mg via oral tablet twice each day (BID), starting with Cycle 7. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m^2 Q3W) plus carboplatin AUC 5 Q3W after Sponsor consultation. Participants may also receive bevacizumab via IV infusion on Day 1 of each 3-week cycle at the Investigator's discretion.
  • Pembrolizumab
  • Carboplatin
  • Paclitaxel
  • Olaparib
  • Bevacizumab
  • Docetaxel
Pembrolizumab+Placebo for OlaparibExperimentalParticipants receive carboplatin/paclitaxel via IV infusion for five 3-week cycles starting in Cycle 1 PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles PLUS placebo for olaparib via oral tablet BID, starting with Cycle 7. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m^2 Q3W) plus carboplatin AUC 5 Q3W after Sponsor consultation. Participants may also receive bevacizumab via IV infusion on Day 1 of each 3-week cycle at the Investigator's discretion.
  • Pembrolizumab
  • Carboplatin
  • Paclitaxel
  • Placebo for olaparib
  • Bevacizumab
  • Docetaxel
Placebo for Pembrolizumab+Placebo for OlaparibActive ComparatorParticipants receive carboplatin/paclitaxel via IV infusion for five 3-week cycles PLUS placebo for pembrolizumab (normal saline or dextrose) via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles PLUS placebo for olaparib via oral tablet BID, starting with Cycle 7. Participants who experience severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel may receive docetaxel (75 mg/m^2 Q3W) plus carboplatin AUC 5 Q3W after Sponsor consultation. Participants may also receive bevacizumab via IV infusion on Day 1 of each 3-week cycle at the Investigator's discretion.
  • Placebo for pembrolizumab
  • Carboplatin
  • Paclitaxel
  • Placebo for olaparib
  • Bevacizumab
  • Docetaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Has histologically confirmed International Federation of Gynecology and Obstetrics
             (FIGO) Stage III or Stage IV EOC (high-grade predominantly serous, endometrioid,
             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 180 days following the last
             dose of pembrolizumab (or pembrolizumab placebo) and olaparib (or olaparib placebo)
             and at least 210 days following the last dose of chemotherapy or bevacizumab (if
             administered) and agrees not to donate eggs (ova, oocytes) to others or freeze/store
             for personal 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, defined as defined as systolic >140 mm Hg or diastolic
             >90 mm Hg documented by 2 blood pressure readings taken at least 1 hour apart. Note:
             This applies only to participants who will receive bevacizumab during the lead-in
             period and should be confirmed prior to the first administration of bevacizumab. Use
             of antihypertensive medications to control blood pressure is allowed.

          -  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 180 days following
             the last dose of pembrolizumab (or pembrolizumab placebo) and olaparib (or olaparib
             placebo) and at least 210 days following the last dose of chemotherapy or bevacizumab
             (if administered)

          -  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

          -  Has received whole blood transfusions in the last 120 days prior to randomization

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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

Measure:PFS Per RECIST 1.1 As Assessed by Blinded Independent Central Review
Time Frame:Up to approximately 6 years
Safety Issue:
Description: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.
Measure:PFS After Next-line Treatment (PFS2) Following Discontinuation of Study Treatment As Assessed by the Investigator
Time Frame:Up to approximately 78 months
Safety Issue:
Description:PFS2 is defined as the time from randomization until PD on next-line treatment or death due to any cause, whichever occurs first. The PFS2 per Investigator assessment will be presented.
Measure:Number of Participants Who Experience an Adverse Event (AE)
Time Frame:Up to approximately 73 months
Safety Issue:
Description: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 presented.
Measure:Number of Participants Who Discontinue Study Treatment Due to an AE
Time Frame:Up to approximately 6 years
Safety Issue:
Description:The number of participants who discontinue study treatment due to an AE will be presented.
Measure:Change from Baseline in Global Health Status/Quality of Life (GHS/QoL) Score Using Questions from the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)
Time Frame:Baseline and End of Study Participation (Up to approximately 6 years)
Safety Issue:
Description:Participants are asked to answer 2 questions from the EORTC QLQ-C30 about their GHS: "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?" Responses are based on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better global health status. The change from baseline in GHS/QoL score of participants will be presented.
Measure:Change from Baseline in Abdominal and Gastrointestinal (Abdominal/GI) Symptoms Score Using the EORTC Quality of Life Questionnaire-Ovarian Cancer (QLQ-OV28) Abdominal/GI Symptom Scale
Time Frame:Baseline and End of Study Participation (Up to approximately 6 years)
Safety Issue:
Description:Participants are asked to answer 6 questions from the EORTC QoL Questionnaire-Ovarian Cancer (QLQ-OV28) abdominal/GI symptom scale about abdominal pain, bloated feeling in abdomen/stomach, changes in clothing fit, changes in bowel habit, flatulence and stomach fullness when eating. Responses are based on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating better abdominal/GI symptoms. The change from baseline in abdominal/GI symptom score of participants will be presented.
Measure:Time to First Subsequent Anti-cancer Treatment (TFST)
Time Frame:Up to approximately 6 years
Safety Issue:
Description:TFST is defined as the time from randomization to initiation of first subsequent anti-cancer treatment or death due to any cause, whichever occurs first. The TFST will be presented.
Measure:Time to Second Subsequent Anti-cancer Treatment (TSST)
Time Frame:Up to approximately 6 years
Safety Issue:
Description:TSST is defined as the time from randomization to initiation of second subsequent anti-cancer treatment or death due to any cause, whichever occurs first. The TSST will be presented.
Measure:Time to Discontinuation of Study Treatment or Death (TDT)
Time Frame:Up to approximately 6 years
Safety Issue:
Description:TDT is defined as the time from the date of randomization to discontinuation of study treatment or death due to any cause, whichever occurs first. The TDT will be presented.
Measure:Pathological Complete Response (pCR) Rate
Time Frame:Up to approximately 30 months
Safety Issue:
Description:pCR is defined as all surgical specimens collected during the interval debulking surgery are microscopically negative for malignancy. The pCR rate for all surgical specimens will be presented.
Measure:Time Without Symptom of Disease Progression or Toxicity of Treatment (TWiST)
Time Frame:Up to approximately 6 years
Safety Issue:
Description:TWiST is defined as the time from randomization to disease progression or treatment-related toxicity, whichever occurs first. The TWiST will be presented.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)

Last Updated

February 5, 2021