Trials / Terminated

TerminatedNCT03209401

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

Status: Terminated
Phase: Phase 1
Study type: Interventional
Enrollment: 23 (actual)

Sponsor: Georgetown University · Academic / Other
Sex: All
Age: 18 Years
Healthy volunteers: Not accepted

Summary

Detailed description

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. Patients will be pre-identified from participating centers as having either a germline deleterious mutation or tumor expression of a deleterious mutation in one of the genes listed below, as determined by Next-generation DNA sequencing (NGS) only, completed prior to enrollment in this protocol. Patients with advanced solid tumor malignancies with the presence of somatic or germline deleterious mutation in a gene(s) critical to DNA 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, and who have an adequate performance status (PS), bone marrow, hepatic, and renal function as well as biopsiable and measurable disease will be screened for enrollment. Appropriate patients will be enrolled in a 3+3 alternating dose escalating fashion, to a maximum dose of niraparib of 300mg daily and a maximum dose of carboplatin area under the curve (AUC) of 4. The 3+3 schema will be employed to insure safety and tolerability. However, within any given cohort, a full contingent of 6 patients (assuming adequate tolerability) will be enrolled to capture a sufficient number of patients and samples for pharmacodynamic assessment of DNA damage. Once the RP2D and schedule are identified, a Phase Ib expansion cohort of 20 additional patients will be enrolled as a pilot subgroup to determine efficacy. Of the 20 patients in this Phase Ib cohort, no more than 10 patients will have underlying breast cancer; and additionally no more than 10 patients may harbor BRCA1 or BRCA2 mutations. To assess the efficacy of poly (ADP-ribose) polymerase (PARP) inhibition and the extent of DNA damage, patients will undergo serial tumor biopsies to measure DNA damage as quantified by levels of ᵞH2AX and RAD51 foci formation, as well as an assessment of PARP inhibitory activity. Tumor biopsies will also be used to assess the mechanisms of resistance to PARP inhibitor-based therapy. Assessment of safety including blood tests, clinic visits and exams will occur weekly at the start of therapy, then will transition to every 3-week clinic visits and exams at the beginning of cycle 4. For the Phase Ib portion, patients will undergo weekly lab work and clinic visits for cycle 1 only. The researchers hypothesize that in this HR deficient patient population, the addition of niraparib to carboplatin will lead to significant anti-tumor responses with acceptable toxicities.

Conditions

Interventions

Type	Name	Description
DRUG	Niraparib	an oral PARP inhibitor
DRUG	Carboplatin	a platinum-based injection

Timeline

Start date: 2017-10-13
Primary completion: 2023-10-16
Completion: 2023-10-16
First posted: 2017-07-06
Last updated: 2024-02-05

Locations

5 sites across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT03209401. Inclusion in this directory is not an endorsement.