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

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

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)

Study Overview

• Status: Completed
• Conditions: Neoplasms; Breast Cancer; Advanced Breast Cancer; Ovarian Cancer; Fallopian Tube Cancer; Metastatic Breast Cancer; Triple Negative Breast Cancer; Peritoneal Cancer; Stage IV Breast Cancer
• Intervention / Treatment: Drug: niraparib; Biological: pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • GSK Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • GSK Investigational Site
    • Scottsdale, Arizona, United States, 85258
      • GSK Investigational Site
  • California
    • Los Angeles, California, United States, 90048
      • GSK Investigational Site
    • San Francisco, California, United States, 94115
      • GSK Investigational Site
    • Stanford, California, United States, 94305
      • GSK Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • GSK Investigational Site
  • Florida
    • Deerfield Beach, Florida, United States, 33442
      • GSK Investigational Site
    • Jacksonville, Florida, United States, 32224
      • GSK Investigational Site
    • Miami, Florida, United States, 33136
      • GSK Investigational Site
    • Orlando, Florida, United States, 32804
      • GSK Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • GSK Investigational Site
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • GSK Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • GSK Investigational Site
    • Boston, Massachusetts, United States, 02111
      • GSK Investigational Site
    • Boston, Massachusetts, United States, 02115
      • GSK Investigational Site
    • Burlington, Massachusetts, United States, 01805
      • GSK Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • GSK Investigational Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • GSK Investigational Site
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • GSK Investigational Site
  • New York
    • New York, New York, United States, 10065
      • GSK Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • GSK Investigational Site
    • Charlotte, North Carolina, United States, 28204
      • GSK Investigational Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • GSK Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • GSK Investigational Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • GSK Investigational Site
    • Nashville, Tennessee, United States, 37203
      • GSK Investigational Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • GSK Investigational Site
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • GSK Investigational Site
  • Washington
    • Seattle, Washington, United States, 98109
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants Reporting Dose-Limiting Toxicities (DLTs)	DLTs are defined as: Any treatment-related Grade >=3 non-hematologic clinical (non-laboratory) adverse event (AE); Any treatment-related Grade 3 or Grade 4 non-hematologic laboratory (lab) abnormality if Medical intervention is required to treat the participant 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 non-hematologic AE leading to <80 percent (%) of an intended dose being administered.	During Cycle 1, ie, during the first 21 days of treatment
Phase 2: Objective Response Rate (ORR) as Measured by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1	ORR is defined as the percentage of participants with a confirmed best overall response of Complete Response (CR) or Partial Response (PR), RECIST v1.1 for target lesions as assessed by the Investigator. CR is defined as disappearance of all target lesions, Any pathological lymph nodes must be <10 millimeters (mm) in the short axis; PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the Baseline sum diameters.	Up to 40 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event was any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. TEAEs were any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment has been administered.	Up to a maximum of 22 months
Phase 2: Number of Participants With TEAEs	An adverse event was any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. TEAEs were any new AE that begins, or any pre-existing condition that worsens in severity, after at least 1 dose of study treatment has been administered.	Up to a maximum of 54 months
Phase 2: Overall Response Rate (ORR) as Measured by Immune-related RECIST (irRECIST)	ORR by irRECIST is defined as the percentage of participants with a confirmed best overall response of CR or PR using irRECIST. Immune related complete response (irCR) is defined as at least two radiographic determinations of CR, at least 4 weeks apart and before Immune related progressive disease (irPD - defined as at least two consecutive radiographic determinations of progressive disease [PD] at least 4 weeks apart) at least 4 weeks apart. Immune related partial response (irPR) defined as at least two radiographic determinations of PR or better at least 4 weeks apart and before irPD (and not qualifying for an irCR).	Up to a maximum of 54 months
Phase 2: Duration of Response (DOR) as Measured by RECIST v1.1	DoR per RECIST v1.1 was defined as the time from first documented evidence of CR or PR until first documented disease progression per RECIST v1.1 based upon investigator assessment or death due to any cause, whichever occurs first, among participants who demonstrated CR or PR as the best overall response per RECIST v1.1. CR is defined as disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeters (mm) in the short axis. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the Baseline sum diameters.	Up to a maximum of 54 months
Phase 2: DOR as Measured by irRECIST	DOR was defined as the time from the initial response (irCR, irPR or irSD) to progression or death, whichever occurs first. Response was to be assessed using the irRECIST. Immune related complete response (irCR) is at least two radiographic determinations of CR at least 4 weeks apart and before Immune related progressive disease (irPD - defined as at least two consecutive radiographic determinations of PD at least 4 weeks apart) at least 4 weeks apart. Immune related partial response (irPR) defined as at least two radiographic determinations of PR or better at least 4 weeks apart and before irPD (and not qualifying for an irCR).	Up to a maximum of 54 months
Phase 2: Disease Control Rate (DCR) as Measured by RECIST v1.1	DCR is defined as the percentage of participants who achieved a CR or PR or stable disease (SD) using RECIST (v1.1) as assessed by the investigator.	Up to 40 weeks
Phase 2: DCR as Measured by irRECIST	DCR is percentage of participants achieving best overall response of confirmed irCR, irPR, or immune-related stable disease (irSD) (lasting at least 5 weeks), according to irRECIST from the first dose date until disease progression/recurrence.	Up to a maximum of 54 months
Phase 2: Progression Free Survival (PFS) as Measured by RECIST v1.1	PFS is defined as the time from first dose of study treatment to the earlier date of assessment of progression or death by any cause in the absence of progression based on the time of first documentation of disease progression per RECIST v1.1. Progression is defined using RECIST v1.1 as a 20% increase in the sum of the diameter of target lesions or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions.	Up to a maximum of 54 months
Phase 2: PFS as Measured by irRECIST	Progression free survival is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever comes first. Progression was to be assessed using the Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST). Immune related progressive disease (irPD) is defined as at least two consecutive radiographic determinations of progressive disease (PD - e.g., appearance of one or more new lesions) at least 4 weeks apart).	Up to a maximum of 54 months
Phase 2: Overall Survival (OS)	OS is defined as the time from date of first dose of study treatment to the date of death by any cause.	Up to a maximum of 54 months
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 (Predose) to 24 Hours Post Dose (AUC [0-24]) of Niraparib	Blood samples were collected at indicated time points. Pharmacokinetic (PK) analysis of Niraparib was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: AUC (0-24) of Major Metabolite of Niraparib (M1)	Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: Minimum Observed Plasma Concentration (Cmin) and Maximum Observed Plasma Concentration (Cmax) of Niraparib	Blood samples were collected at indicated time points. Pharmacokinetic analysis of Niraparib was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: Cmin and Cmax of Major Metabolite of Niraparib (M1)	Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: Apparent Oral Clearance (CL/F) of Niraparib	Blood samples were planned to be collected for to determine CL/F of Niraparib.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: Apparent Oral Clearance (CL/F) of Major Metabolite of Niraparib (M1)	Blood samples were planned to be collected for to determine CL/F of major metabolite (M1) of Niraparib.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: Volume of Distribution (Vz/F) of Niraparib	Blood samples were planned to be collected for to determine Vz/F of Niraparib.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: Volume of Distribution (Vz/F) of Major Metabolite of Niraparib (M1)	Blood samples were planned to be collected for to determine Vz/F of major metabolite (M1) of Niraparib.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days)
Phase 1: AUC at Steady State (AUC,ss) of Niraparib	Blood samples were collected at indicated time points. Pharmacokinetic analysis of Niraparib was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days)
Phase 1: AUC,ss of Major Metabolite of Niraparib (M1)	Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days)
Phase 1: Minimum Observed Plasma Concentration at Steady State (Cmin,ss) and Maximum Observed Plasma Concentration at Steady State (Cmax,ss) of Niraparib	Blood samples were collected at indicated time points. Pharmacokinetic analysis of Niraparib was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days)
Phase 1: Cmin,ss and Cmax,ss of Major Metabolite of Niraparib (M1)	Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.	Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1(each cycle of 21 days)
Phase 2: Plasma Concentrations of Niraparib	Blood samples were collected by sparse PK sampling to analyze plasma concentration of Niraparib.	Pre-dose and 2 Hours post-dose on Cycle 1 Day 1; Pre-dose and 2 Hours post-dose on Cycle 2 Day 1(each cycle of 21 days)
Phase 2: Plasma Concentrations of Major Metabolite of Niraparib (M1)	Blood samples were collected by sparse PK sampling to analyze plasma concentration of major metabolite of Niraparib (M1).	Pre-dose and 2 Hours post-dose on Cycle 1 Day 1; Pre-dose and 2 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days)

Collaborators and Investigators

• Sponsor: Tesaro, Inc.
• Collaborators: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Farkkila 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, Farkkila 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 Aug 1;5(8):1141-1149. doi: 10.1001/jamaoncol.2019.1048.
• 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 Aug 1;5(8):1132-1140. doi: 10.1001/jamaoncol.2019.1029.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2016
• Primary Completion (Actual): May 14, 2018
• Study Completion (Actual): September 17, 2021

Study Registration Dates

• First Submitted: January 8, 2016
• First Submitted That Met QC Criteria: January 13, 2016
• First Posted (Estimate): January 18, 2016

Study Record Updates

• Last Update Posted (Actual): December 1, 2022
• Last Update Submitted That Met QC Criteria: November 7, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: PARP inhibitor; Niraparib; Pembrolizumab; PD-1; Keynote; TOPACIO
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Breast Diseases; Fallopian Tube Diseases; Breast Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Poly(ADP-ribose) Polymerase Inhibitors; Pembrolizumab; Niraparib
• Other Study ID Numbers: 213363; 3000-PN162-01-001 (Other Identifier: Tesaro)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No