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

• ClinicalTrials.gov Identifier: NCT02657889
• Recruitment Status: Active, not recruiting
• First Posted: January 18, 2016
• Results First Posted: February 11, 2020
• Last Update Posted: January 13, 2021
• Sponsor: Tesaro, Inc.
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Tesaro, Inc.

Tracking Information

• First Submitted Date: January 8, 2016
• First Posted Date: January 18, 2016
• Results First Submitted Date: December 17, 2019
• Results First Posted Date: February 11, 2020
• Last Update Posted Date: January 13, 2021
• Actual Study Start Date: March 9, 2016
• Actual Primary Completion Date: May 14, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 17, 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 (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 ]

Current Secondary Outcome Measures (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 (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: Niraparib in Combination With Pembrolizumab in Patients With Triple-negative Breast Cancer or Ovarian Cancer
• 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
• 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Neoplasms
• Triple Negative Breast Cancer
• Ovarian Cancer
• Breast Cancer
• Metastatic Breast Cancer
• Advanced Breast Cancer
• Stage IV Breast Cancer
• Fallopian Tube Cancer
• Peritoneal Cancer

Intervention

• Drug: niraparib
• Biological: pembrolizumab

Study Arms

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 *

• Färkkilä A, Gulhan DC, Casado J, Jacobson CA, Nguyen H, Kochupurakkal B, Maliga Z, Yapp C, Chen YA, Schapiro D, Zhou Y, Graham JR, Dezube BJ, Munster P, Santagata S, Garcia E, Rodig S, Lako A, Chowdhury D, Shapiro GI, Matulonis UA, Park PJ, Hautaniemi S, Sorger PK, Swisher EM, D'Andrea AD, Konstantinopoulos PA. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat Commun. 2020 Mar 19;11(1):1459. doi: 10.1038/s41467-020-15315-8. Erratum in: Nat Commun. 2020 May 18;11(1):2543.
• Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, Van Le L, Sachdev JC, Chapman-Davis E, Colon-Otero G, Penson RT, Matulonis UA, Kim YB, Moore KN, Swisher EM, Färkkilä A, D'Andrea A, Stringer-Reasor E, Wang J, Buerstatte N, Arora S, Graham JR, Bobilev D, Dezube BJ, Munster P. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1048. [Epub ahead of print]
• Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner-Hendrickson AE, Forero A, Anders C, Wulf GM, Dillon P, Lynce F, Zarwan C, Erban JK, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube BJ, Telli ML. Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol. 2019 Jun 13. doi: 10.1001/jamaoncol.2019.1029. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 4, 2020): 122
• Original Estimated Enrollment (submitted: January 13, 2016): 114
• Estimated Study Completion Date: April 30, 2021
• Actual Primary Completion Date: May 14, 2018 (Final data collection date for primary outcome measure)

Eligibility 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02657889
• Other Study ID Numbers: 213363; 3000-PN162-01-001 ( Other Identifier: Tesaro )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Tesaro, Inc.
• Study Sponsor: Tesaro, Inc.
• Collaborators: Merck Sharp & Dohme Corp.

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: Tesaro, Inc.
• Verification Date: December 2020