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

Breast Cancer Clinical Trial

— TOPACIO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02657889
• Other study ID #: 213363
• Secondary ID: 3000-PN162-01-00
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 15, 2016
• Est. completion date: September 17, 2021

Study information

• Verified date: November 2022
• Source: Tesaro, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 122
• Est. completion date: September 17, 2021
• Est. primary completion date: May 14, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

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

Intervention

Drug:
• niraparib

Biological:
• pembrolizumab

Locations

Country	Name	City	State
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Burlington	Massachusetts
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Charlottesville	Virginia
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Covington	Louisiana
United States	GSK Investigational Site	Deerfield Beach	Florida
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Germantown	Tennessee
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Morristown	New Jersey
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Rochester	Minnesota
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Scottsdale	Arizona
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Stanford	California
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Tesaro, Inc.	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)