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Niraparib in Combination With Pembrolizumab in Patients With Triple-negative Breast Cancer or Ovarian Cancer (TOPACIO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02657889
Recruitment Status : Active, not recruiting
First Posted : January 18, 2016
Results First Posted : February 11, 2020
Last Update Posted : February 11, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Tesaro, Inc.

Brief Summary:
This Phase 1/2 study will evaluate the safety and efficacy of combination treatment with niraparib and pembrolizumab (MK-3475) in patients with advanced or metastatic triple-negative breast cancer or recurrent ovarian cancer. (KEYNOTE-162)

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Ovarian Cancer Breast Cancer Metastatic Breast Cancer Advanced Breast Cancer Stage IV Breast Cancer Fallopian Tube Cancer Peritoneal Cancer Drug: niraparib Biological: pembrolizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 122 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Clinical Study of Niraparib in Combination With Pembrolizumab (MK-3475) in Patients With Advanced or Metastatic Triple-Negative Breast Cancer and in Patients With Recurrent Ovarian Cancer
Study Start Date : March 2016
Actual Primary Completion Date : May 2018
Estimated Study Completion Date : March 2020


Arm Intervention/treatment
Experimental: niraparib plus pembrolizumab

Phase 1: Dose-escalation: ascending doses of niraparib up to 300mg/day orally (PO) on Days 1-21 and pembrolizumab 200mg intravenously (IV) on Day 1 of each 21-day cycle

Phase 2: niraparib (recommended Phase 2 dose) in combination with pembrolizumab 200mg IV on Day 1 of each 21-day cycle

Drug: niraparib
Biological: pembrolizumab



Primary Outcome Measures :
  1. Phase 1: Number of Subjects Reporting Dose-Limiting Toxicities (DLTs) [ Time Frame: During Cycle 1, ie, during the first 21 days of treatment ]

    DLTs are defined as:

    Any treatment-related Grade ≥ 3 non-hematologic clinical (non-laboratory) AE

    Any treatment-related Grade 3 or Grade 4 non-hematologic lab abnormality if:

    • Medical intervention is required to treat the patient, or
    • The abnormality leads to hospitalization, or
    • The abnormality persists for ≥ 7 days.

    Any treatment-related hematologic toxicity specifically defined as:

    • Thrombocytopenia Grade 4 for ≥ 7 days, or Grade 3 or 4 associated with bleeding or requiring platelet transfusion;
    • Neutropenia Grade 4 for ≥ 7 days, or Grade 3 or 4 associated with infection or febrile neutropenia;
    • Anemia Grade 4, or Grade 3 or 4 requiring blood transfusion.

    Any treatment-related AE leading to niraparib dose interruption per the following criteria:

    • A dose interruption for a non-DLT lab abnormality lasting ≥ 14 days.
    • A dose in interruption per dose modification rules for nonhematologic AE leading to < 80% of an intended dose being administered.

  2. Phase 2: Objective Response Rate (ORR) [ Time Frame: Up to 40 weeks ]
    ORR is defined as the percentage of patients who achieved a best overall response of Complete Response (CR) or Partial Response (PR), per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions as assessed by the Investigator: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.


Secondary Outcome Measures :
  1. To Evaluate the Safety and Tolerability of Combination Treatment With Niraparib and Pembrolizumab Using Common Terminology Criteria for Adverse Events (CTCAE, v4.03) [ Time Frame: AEs were collected up to 90 days following the last dose of study treatment, where the median duration of treatment was 3 months. ]
    Percentage of patients with at least 1 Treatment-Emergent Adverse Event. Refer to the adverse event tables for specific details.

  2. Phase 2: Overall Response Rate (ORR) as Measured by Immune-related RECIST (irRECIST) [ Time Frame: Radiographic evaluations were conducted every 9 weeks while on study treatment (every 12 weeks after 1 year of scans) independent of cycle delays and/or dose interruptions, and/or at any time when progression of disease is suspected. ]
    ORR by irRECIST is defined as the proportion of patients who achieved a best overall response of complete response (CR) or partial response (PR) using immune-related RECIST criteria.

  3. Phase 2: Duration of Response (DOR) [ Time Frame: From first documentation of response (CR or PR) using RECIST (v1.1) as assessed by the Investigator until time of first documented progression. ]
    From first documentation of response (CR or PR) using RECIST (v1.1) as assessed by the investigator until time of first documented progression or death by any cause. No maximum timeframe was specified in the protocol.

  4. Phase 2: Disease Control Rate (DCR) [ Time Frame: Up to 40 weeks ]
    DCR is defined as the percentage of patients who achieved a CR or PR or stable disease (SD) using RECIST (v1.1) as assessed by the Investigator.

  5. Phase 2: Progression Free Survival (PFS) [ Time Frame: From date of first dose to the earlier date of assessment of progression of death by any cause in the absence of progression. ]
    From date of first dose to the earlier date of assessment of progression or death by any cause in the absence of progression. No maximum timeframe was specified in the protocol.

  6. Phase 2: Overall Survival (OS) [ Time Frame: From date of first dose to the date of death by any cause. ]
    Patients were followed off treatment every 90 days for survival status. Overall survival is defined as the time from first dose to the date of death by any cause. No maximum timeframe was specified in the protocol.

  7. Phase 1 and Phase 2: To Evaluate the Pharmacokinetics (PK) of Niraparib and Associated Major Metabolite M1 During Combination Treatment. [ Time Frame: Approximately 9 months ]
    Area Under the Curve (AUC), Minimum Concentration (Cmin), Maximum Concentration (Cmax), Clearance After Oral Administration (CL/F), Volume of Distribution After Oral Administration (Vz/F), AUC at Steady State (AUCss), Cmin at Steady State (Cmin,ss), Cmax at Steady State (Cmax,ss).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Main Inclusion Criteria:

  • Patient has histologically proven advanced (unresectable) or metastatic cancer as outlined below according to study phase and disease type:

    1. Phase 1 patients (breast or ovarian cancer)

      • Patients with advanced or metastatic breast cancer must have disease that is HER2-negative, estrogen receptor-negative, and progesterone receptor-negative (ie, TNBC). Patients with advanced or metastatic disease may have up to 4 lines of cytotoxic therapy. Neoadjuvant and adjuvant therapies are not counted towards lines of therapy.
      • Patients must have any epithelial (ie, serous, endometroid, mucinous, clear cell) ovarian, fallopian tube, or primary peritoneal cancer. Patients must have experienced a response lasting at least 6 months to first-line platinum-based therapy but currently considered to have platinum-resistant disease per investigator's assessment (e.g, patient is not eligible for further platinum containing treatment). Patients may have received up to 5 lines of cytotoxic therapy for advanced or metastatic cancer. Neoadjuvant and adjuvant therapies are not counted towards lines of therapy.
    2. Phase 2 patients (breast or ovarian cancer)

      • Patients with advanced or metastatic breast cancer must have TNBC. Patients with advanced or metastatic disease may have received up to 2 lines of cytotoxic therapy. Adjuvant and/or neoadjuvant therapies are not counted in the number of lines of therapy. TNBC patients who have previously received platinum chemotherapy in the metastatic setting are allowed to enroll in the study as long as they did not progress while on or within 8 weeks from the day of the last platinum administration.
      • Patients must have with high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer. Patients must have experienced a response lasting at least 6 months to first-line platinum-based therapy but currently considered to have platinum-resistant disease per investigator's assessment (e.g, patient is not eligible for further platinum containing treatment). Patients may have had up to 4 lines of cytotoxic therapy for advanced or metastatic cancer. Neoadjuvant, adjuvant, and the combination of both will be considered as one line of therapy.
  • Archival tumor tissue available or a fresh biopsy must be obtained prior to study treatment initiation
  • Measurable lesions by RECIST v1.1
  • Eastern Cooperative Oncology Group (ECOG) 0 or 1
  • Adequate organ function
  • Able to take oral medications
  • Female patient, if of childbearing potential, has a negative serum pregnancy test within 72 hours of taking study medication and agrees to abstain from activities that could result in pregnancy from enrollment through 120 days after the last dose of study treatment
  • Male patient agrees to use an adequate method of contraception

Main Exclusion Criteria:

  • Patients with primary platinum refractory ovarian cancer (ie, progressive disease on or within 6 months of first-line platinum therapy)
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis Note: Patients previously treated for brain metastases may be able to participate provided they are stable
  • Patient has a known additional malignancy that progressed or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer
  • Poor medical risk
  • Condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment.
  • Pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study
  • Immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Known active hepatitis B or hepatitis C
  • Active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Prior treatment with a known poly(ADP-ribose) polymerase (PARP) inhibitor
  • Heart-rate corrected QT interval (QTc) prolongation > 470 msec at screening
  • Known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02657889


Locations
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United States, Alabama
Birmingham, Alabama, United States, 35294
United States, Arizona
Scottsdale, Arizona, United States, 85258
Scottsdale, Arizona, United States, 85259
United States, California
Los Angeles, California, United States, 90048
San Francisco, California, United States, 94115
Stanford, California, United States, 94305
United States, District of Columbia
Washington, District of Columbia, United States, 20007
United States, Florida
Jacksonville, Florida, United States, 32224
Miami, Florida, United States, 33136
Orlando, Florida, United States, 32804
United States, Georgia
Atlanta, Georgia, United States, 30342
United States, Illinois
Chicago, Illinois, United States, 60637
United States, Louisiana
Covington, Louisiana, United States, 70433
United States, Massachusetts
Boston, Massachusetts, United States, 02111
Boston, Massachusetts, United States, 02215
Burlington, Massachusetts, United States, 01805
United States, Michigan
Detroit, Michigan, United States, 48201
United States, Minnesota
Rochester, Minnesota, United States, 55905
United States, New Jersey
Morristown, New Jersey, United States, 07960
United States, New York
Lake Success, New York, United States, 11042
New York, New York, United States, 10065
United States, North Carolina
Chapel Hill, North Carolina, United States, 27599
Charlotte, North Carolina, United States, 28204
United States, Ohio
Cleveland, Ohio, United States, 44106
United States, Oklahoma
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Memphis, Tennessee, United States, 38104
Nashville, Tennessee, United States, 37203
United States, Texas
San Antonio, Texas, United States, 78229
United States, Virginia
Charlottesville, Virginia, United States, 22908
United States, Washington
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Tesaro, Inc.
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Bruce Dezube, MD Tesaro, Inc.
  Study Documents (Full-Text)

Documents provided by Tesaro, Inc.:
Study Protocol  [PDF] March 1, 2017
Statistical Analysis Plan  [PDF] March 21, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Tesaro, Inc.
ClinicalTrials.gov Identifier: NCT02657889    
Other Study ID Numbers: 3000-PN162-01-001
First Posted: January 18, 2016    Key Record Dates
Results First Posted: February 11, 2020
Last Update Posted: February 11, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Tesaro, Inc.:
PARP inhibitor
PD-1
Niraparib
Pembrolizumab
Keynote
TOPACIO
Additional relevant MeSH terms:
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Breast Neoplasms
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Triple Negative Breast Neoplasms
Fallopian Tube Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Fallopian Tube Diseases
Pembrolizumab
Niraparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action