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

• ClinicalTrials.gov Identifier: NCT02657889
• Recruitment Status: Completed
• First Posted: January 18, 2016
• Results First Posted: February 11, 2020
• Last Update Posted: December 1, 2022
• Sponsor: Tesaro, Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Tesaro, Inc.

Study Description

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
Neoplasms; 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

Study Design

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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Number of Participants 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) 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.
2. Phase 2: Objective Response Rate (ORR) as Measured by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 [ Time Frame: Up to 40 weeks ]
   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.

Secondary Outcome Measures :

1. Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to a maximum of 22 months ]
   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.
2. Phase 2: Number of Participants With TEAEs [ Time Frame: Up to a maximum of 54 months ]
   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.
3. Phase 2: Overall Response Rate (ORR) as Measured by Immune-related RECIST (irRECIST) [ Time Frame: Up to a maximum of 54 months ]
   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).
4. Phase 2: Duration of Response (DOR) as Measured by RECIST v1.1 [ Time Frame: Up to a maximum of 54 months ]
   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.
5. Phase 2: DOR as Measured by irRECIST [ Time Frame: Up to a maximum of 54 months ]
   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).
6. Phase 2: Disease Control Rate (DCR) as Measured by RECIST v1.1 [ Time Frame: Up to 40 weeks ]
   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.
7. Phase 2: DCR as Measured by irRECIST [ Time Frame: Up to a maximum of 54 months ]
   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.
8. Phase 2: Progression Free Survival (PFS) as Measured by RECIST v1.1 [ Time Frame: Up to a maximum of 54 months ]
   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.
9. Phase 2: PFS as Measured by irRECIST [ Time Frame: Up to a maximum of 54 months ]
   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).
10. Phase 2: Overall Survival (OS) [ Time Frame: Up to a maximum of 54 months ]
    OS is defined as the time from date of first dose of study treatment to the date of death by any cause.
11. Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 (Predose) to 24 Hours Post Dose (AUC [0-24]) of Niraparib [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic (PK) analysis of Niraparib was conducted using standard non-compartmental analysis.
12. Phase 1: AUC (0-24) of Major Metabolite of Niraparib (M1) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.
13. Phase 1: Minimum Observed Plasma Concentration (Cmin) and Maximum Observed Plasma Concentration (Cmax) of Niraparib [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of Niraparib was conducted using standard non-compartmental analysis.
14. Phase 1: Cmin and Cmax of Major Metabolite of Niraparib (M1) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.
15. Phase 1: Apparent Oral Clearance (CL/F) of Niraparib [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were planned to be collected for to determine CL/F of Niraparib.
16. Phase 1: Apparent Oral Clearance (CL/F) of Major Metabolite of Niraparib (M1) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were planned to be collected for to determine CL/F of major metabolite (M1) of Niraparib.
17. Phase 1: Volume of Distribution (Vz/F) of Niraparib [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were planned to be collected for to determine Vz/F of Niraparib.
18. Phase 1: Volume of Distribution (Vz/F) of Major Metabolite of Niraparib (M1) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 1 Day 1 (each cycle of 21 days) ]
    Blood samples were planned to be collected for to determine Vz/F of major metabolite (M1) of Niraparib.
19. Phase 1: AUC at Steady State (AUC,ss) of Niraparib [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of Niraparib was conducted using standard non-compartmental analysis.
20. Phase 1: AUC,ss of Major Metabolite of Niraparib (M1) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.
21. Phase 1: Minimum Observed Plasma Concentration at Steady State (Cmin,ss) and Maximum Observed Plasma Concentration at Steady State (Cmax,ss) of Niraparib [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1 (each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of Niraparib was conducted using standard non-compartmental analysis.
22. Phase 1: Cmin,ss and Cmax,ss of Major Metabolite of Niraparib (M1) [ Time Frame: Pre-dose and 1, 2, 4, 6, 8, 24 Hours post-dose on Cycle 2 Day 1(each cycle of 21 days) ]
    Blood samples were collected at indicated time points. Pharmacokinetic analysis of major metabolite of Niraparib (M1) was conducted using standard non-compartmental analysis.
23. Phase 2: Plasma Concentrations of Niraparib [ Time Frame: 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) ]
    Blood samples were collected by sparse PK sampling to analyze plasma concentration of Niraparib.
24. Phase 2: Plasma Concentrations of Major Metabolite of Niraparib (M1) [ Time Frame: 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) ]
    Blood samples were collected by sparse PK sampling to analyze plasma concentration of major metabolite of Niraparib (M1).

Eligibility Criteria

• 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)

Contacts and Locations

Locations

United States, Alabama

GSK Investigational Site

Birmingham, Alabama, United States, 35249

United States, Arizona

GSK Investigational Site

Phoenix, Arizona, United States, 85054

GSK Investigational Site

Scottsdale, Arizona, United States, 85258

United States, California

GSK Investigational Site

Los Angeles, California, United States, 90048

GSK Investigational Site

San Francisco, California, United States, 94115

GSK Investigational Site

Stanford, California, United States, 94305

United States, District of Columbia

GSK Investigational Site

Washington, District of Columbia, United States, 20007

United States, Florida

GSK Investigational Site

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

United States, Illinois

GSK Investigational Site

Chicago, Illinois, United States, 60637

United States, Louisiana

GSK Investigational Site

Covington, Louisiana, United States, 70433

United States, Massachusetts

GSK Investigational Site

Boston, Massachusetts, United States, 02111

GSK Investigational Site

Boston, Massachusetts, United States, 02114

GSK Investigational Site

Boston, Massachusetts, United States, 02115

GSK Investigational Site

Burlington, Massachusetts, United States, 01805

United States, Michigan

GSK Investigational Site

Detroit, Michigan, United States, 48201

United States, Minnesota

GSK Investigational Site

Rochester, Minnesota, United States, 55905

United States, New Jersey

GSK Investigational Site

Morristown, New Jersey, United States, 07962

United States, New York

GSK Investigational Site

New York, New York, United States, 10065

United States, North Carolina

GSK Investigational Site

Chapel Hill, North Carolina, United States, 27514

GSK Investigational Site

Charlotte, North Carolina, United States, 28204

United States, Ohio

GSK Investigational Site

Cleveland, Ohio, United States, 44106

United States, Oklahoma

GSK Investigational Site

Oklahoma City, Oklahoma, United States, 73104

United States, Tennessee

GSK Investigational Site

Germantown, Tennessee, United States, 38138

GSK Investigational Site

Nashville, Tennessee, United States, 37203

United States, Texas

GSK Investigational Site

San Antonio, Texas, United States, 78229

United States, Virginia

GSK Investigational Site

Charlottesville, Virginia, United States, 22903

United States, Washington

GSK Investigational Site

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Tesaro, Inc.

Merck Sharp & Dohme LLC

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by Tesaro, Inc.:

Study Protocol  [PDF] March 1, 2017

Statistical Analysis Plan  [PDF] March 21, 2019

More Information

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

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.

• Responsible Party: Tesaro, Inc.
• ClinicalTrials.gov Identifier: NCT02657889
• Other Study ID Numbers: 213363; 3000-PN162-01-001 ( Other Identifier: Tesaro )
• First Posted: January 18, 2016
• Results First Posted: February 11, 2020
• Last Update Posted: December 1, 2022
• Last Verified: November 2022

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:

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 Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Fallopian Tube Diseases; Pembrolizumab; Niraparib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors