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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.

Tracking Information
First Submitted Date  ICMJE January 8, 2016
First Posted Date  ICMJE January 18, 2016
Results First Submitted Date  ICMJE December 17, 2019
Results First Posted Date  ICMJE February 11, 2020
Last Update Posted Date February 11, 2020
Study Start Date  ICMJE March 2016
Actual Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 4, 2020)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 13, 2016)
  • Evaluate dose-limiting toxicities (DLTs) of combination treatment with niraparib and pembrolizumab during the first cycle of treatment, and to establish a recommended Phase 2 dose (RP2D) and schedule [ Time Frame: Phase 1: Approximately 9 months ]
  • To estimate the clinical activity of combination treatment with niraparib and pembrolizumab in terms of objective response rate (ORR) as assessed by the Investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: Phase 2: Approximately 12 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 4, 2020)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2016)
  • 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: Approximately 18 months ]
  • Overall Response Rate (ORR) [ Time Frame: Approximately 12 months ]
    as measured by immune-related RECIST (irRECIST)
  • Duration of Response (DOR) [ Time Frame: Approximately 18 months ]
    defined as the time from first documentation of response (CR or PR) until the time of first documentation of disease progression
  • Disease Control Rate (DCR) [ Time Frame: Approximately 12 months ]
    defined as the percentage of patients who have achieved CR, PR, or stable disease (SD) per RECIST or irRECIST
  • Progression Free Survival (PFS) [ Time Frame: Approximately 18 months ]
    defined as the time from first dose to the earlier date of assessment of progression, or death by any cause in the absence of progression, by RECIST or irRECIST
  • Overall Survival (OS) [ Time Frame: Approximately 2 years ]
    as measured from the date of first dose to the date of death by any cause
  • To evaluate the Area Under the Curve (AUC), Minimum concentration (Cmin) [ Time Frame: Approximately 9 months ]
  • Maximum Concentration (Cmax) [ Time Frame: Approximately 9 months ]
  • Clearance after oral administration (CL/F) [ Time Frame: Approximately 9 months ]
  • Volume of Distribution after oral administration (Vz/F) [ Time Frame: Approximately 9 months ]
  • AUC at steady state (AUCss) [ Time Frame: Approximately 9 months ]
  • Cmin at steady state (Cmin,ss) [ Time Frame: Approximately 9 months ]
    and Cmax at steady state (Cmax,ss)
  • Cmax at steady state (Cmax,ss) [ Time Frame: Approximately 9 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Niraparib in Combination With Pembrolizumab in Patients With Triple-negative Breast Cancer or Ovarian Cancer
Official Title  ICMJE 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
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Triple Negative Breast Cancer
  • Ovarian Cancer
  • Breast Cancer
  • Metastatic Breast Cancer
  • Advanced Breast Cancer
  • Stage IV Breast Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
Intervention  ICMJE
  • Drug: niraparib
  • Biological: pembrolizumab
Study Arms  ICMJE 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

Interventions:
  • Drug: niraparib
  • Biological: pembrolizumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 4, 2020)
122
Original Estimated Enrollment  ICMJE
 (submitted: January 13, 2016)
114
Estimated Study Completion Date  ICMJE March 2020
Actual Primary Completion Date May 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02657889
Other Study ID Numbers  ICMJE 3000-PN162-01-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Tesaro, Inc.
Study Sponsor  ICMJE Tesaro, Inc.
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Study Director: Bruce Dezube, MD Tesaro, Inc.
PRS Account Tesaro, Inc.
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP