Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies

NCT03209401 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 2017-0085
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 5

Brief Summary

This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients with advanced, solid tumor malignancies who have pre-identified deleterious germline or somatic mutations in the homologous recombination deoxyribonucleic acid (DNA) repair pathway (HR deficient). The trial is designed to assess the efficacy and safety of niraparib plus carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the recommended phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

Conditions

Solid Tumor, Adult; Homologous Recombination Deficiency

Keywords

Niraparib; Carboplatin

Outcome Measures

Primary Outcomes (2)

• Grade 3 and 4 toxicities

  Phase Ia Primary Endpoint - The number of grade 3 and 4 toxicities according to NCI CTCAE; Version 4.0 that occur after Cycle 1, Day 1 will be recorded at each study visit.

  36 months

• Anti-tumor efficacy by overall response rate

  Phase Ib Primary Endpoint - ORR is defined as the proportion of patients whose best overall response recorded during the treatment is either complete response or partial response according to the RECIST v1.1.

  36 months

Secondary Outcomes (3)

• Median survival

  36 months

• Median progression free survival

  36 months

• Disease control rate

  36 months

Study Arms (1)

Niraparib and Carboplatin

EXPERIMENTAL

Niraparib will be administered orally, once daily for 21 days of each 21-day cycle in escalating doses depending on cohort patient is assigned to. Carboplatin will be administered via an injection on Day 2 of a given 21-day cycle. The dose a patient receives will depend on which cohort the patient is assigned to.

Drug: Niraparib; Drug: Carboplatin

Interventions

Niraparib DRUG

an oral PARP inhibitor

Also known as: MK-4827

Niraparib and Carboplatin

Carboplatin DRUG

a platinum-based injection

Also known as: Paraplatin

Niraparib and Carboplatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients PRE-identified as having either a germline deleterious mutation or tumor expression of a deleterious mutation) as determined by Next-generation DNA sequencing only, in at least one gene involved in DNA damage repair through homologous recombination including but not limited to: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC.
• The determination of a deleterious mutation must be supported in the documentation included in the testing, and should include clinical, or pre-clinical literature to support the finding that a specific mutation results in impaired function of the gene, and thus impaired DNA repair through homologous recombination. Variants of unknown significance will not be eligible.
• Advanced, solid tumor malignancy that is amenable to biopsy. Patient must consent to 4 mandatory biopsies during study
• Life expectancy of more than 3 months
• Age ≥ 18 years
• Measurable disease by RECIST v1.1 criteria (tumor ≥ 1 cm in longest diameter on axial image on computed tomography (CT) or magnetic resonance imaging (MRI) and/or lymph node(s) ≥ 1.5 cm in short axis on CT or MRI) on baseline imaging
• ECOG performance status (PS) of 0 to 1 (Table 10, Appendix A)
• Patients who have received and failed, or have been intolerant to, standard first line therapies known to confer clinical benefit. Patients who refuse standard therapy would also be eligible, as long as their refusal is documented.
• Patients with a standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs):
• QTc interval at screening \< 481 msec
• Resting heart rate 50-90bpm
• Adequate hepatic, bone marrow, and renal function at the time of enrollment:
• Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin ≥ 9.0 g/dL. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 2 weeks before obtaining sample
• Renal function: Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73 m2
• Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 × the upper normal limit of institution's normal range. For subjects with liver metastases, AST and ALT \< 5 × the upper normal limit of institution's normal range, and total bilirubin \>1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia

You may not qualify if:

• Prior disease progression while receiving platinum chemotherapy or platinum chemotherapy within the last 6 months
• For patients who received platinum-based adjuvant chemotherapy, at least 6 months must have passed between the last dose of platinum-based therapy and the development of metastatic disease. For breast cancer patients, at least 12 months must have passed between the last dose of platinum-based therapy and the development of metastatic disease
• Prior PARP inhibitor-based therapy
• Known or suspected CNS metastases, unless at least one month has passed since last local CNS therapy and there is no evidence for recurrent or progressive CNS disease on follow up imaging. Participants may remain on steroids for CNS disease if they are taking a stable dose
• Active severe infection, or known chronic infection with HIV or hepatitis B virus (testing not required prior to enrollment)
• Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months. Additionally, patients must not have QT prolongation greater than or equal to 481 milliseconds
• Life-threatening visceral disease or other severe concurrent disease that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Presence of a psychiatric illness or social situation that would limit compliance with study requirements
• Women who are pregnant or breastfeeding
• Clinically significant peripheral neuropathy at the time of enrollment (defined in the NCI CTCAE v4.0) as grade 2 or greater neurosensory or neuromotor toxicity)
• Patients must not have had investigational therapy administered ≤4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
• Patients must not have had radiotherapy encompassing \>20% of the bone marrow
• Patients must not have a known hypersensitivity to the components of niraparib or the excipients
• Patients must not have had any known, persistent \> Grade 2 toxicity from prior cancer therapy

Sponsors & Collaborators

• Georgetown University: lead
• Tesaro, Inc.: collaborator
• Oregon Health and Science University: collaborator

Study Sites (5)

Yale University, Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20057, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

MeSH Terms

Interventions

niraparib; Carboplatin

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals

Study Officials

• Claudine Isaacs, MD

  Lombardi Comprehensive Cancer Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The Phase Ia portion of the trial will be conducted in a 3+3 design, enrolling patients in cohorts of 3 patients each to insure safety and tolerability. There will be a Phase Ib expansion cohort including 20 patients to further assess the efficacy of niraparib plus carboplatin, using the RP2D and schedule from Phase Ia.

Study Record Dates

• First Submitted: July 3, 2017
• First Posted: July 6, 2017
• Study Start: October 13, 2017
• Primary Completion: October 16, 2023
• Study Completion: October 16, 2023
• Last Updated: February 5, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)