Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Participants will receive a starting dose of 100 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Early Phase Cancer Clinical Trials Recruitment

Early Phase Clinical Trials Recruitment

Pamela Munster, MD

The purpose of this phase 1 clinical trials is to determine whether niraparib (a Poly (ADP-ribose) polymerase inhibitor (PARPi)) can be safely combined with irinotecan with manageable toxicity and reasonable efficacy. Emerging evidence suggest that PARPi is an effective therapeutic strategy in a wider subset of solid tumors that may have defective homologous recombination (HR) or DNA repair gene mutations. BReast CAncer gene (BRCA), partner and localizer of BRCA2 (PALB2), and various other DNA repair germline mutations predispose carriers to cancers of the breast, ovaries, pancreas, prostate and melanoma. A number of preclinical studies have demonstrated that PARP inhibitors can work as chemopotentiators. There is significant interest in this combination, and the recommended phase II dose will be used in the upcoming NCI ComboMatch trial.

This is an open label, non-randomized phase Ib dose finding study of niraparib and irinotecan combination therapy. For this study, individuals with metastatic solid tumor malignancies and BRCA1/2, ataxia telangiectasia mutated gene (ATM), or PALB2 mutations will be enrolled with specific tumors of interest including gastrointestinal cancers (e.g. colon, pancreas, gastric, cholangiocarcinoma), ovarian cancer, and breast cancer.

PRIMARY OBJECTIVES:

I. To assess safety and tolerability of niraparib and irinotecan combination therapy in patients with metastatic solid tumor malignancies and BRCA1/2, ATM, or PALB2 mutations.

II. To determine the MTD and recommended phase II dose of niraparib with irinotecan combination therapy.

SECONDARY OBJECTIVES:

I. To determine the preliminary efficacy of niraparib and irinotecan combination therapy in patients with metastatic solid tumor malignancies and BRCA1/2, ATM, or PALB2 mutations.

OVERVIEW:

Participants will be treated in cohorts of size three to six, and the dosage will be escalated if the clinical toxicity is acceptable. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, start of new anti-cancer therapy, or death. Participants will be followed for 30 days after study drug discontinuation for safety and every 12 weeks (+/- 2 weeks) for up to 2 years after start of therapy until disease progression or death from any cause (whichever occurs first).

Combination Therapy in Cancers With Mutations in DNA Repair Genes

Combination Therapy of Niraparib and Irinotecan in Cancers With Mutations in DNA Repair Genes

The percentage of participants with treatment-emergent adverse events as classified and graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be reported

The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 33% or occurs within at most one out of six patients treated at any given dose level.

The percentage of participants with documented dose-limiting toxicities will be reported by dose level.

The RP2D will be selected based on the evaluation of dose-limiting toxicities and adverse events measured using CTCAE v5.0.

Defined as the proportion of participants who achieve a Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 best overall response of confirmed complete response (CR) or confirmed partial response (PR)

Defined as the duration of time from when measurement criteria are met for CR or PR (whichever is first recorded) until the date that recurrent/ progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).

Defined as the duration of time from measurement criteria are met for SD or better until the date that recurrent/ progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).

Defined as the duration of time from start of treatment to time of disease recurrence/ progression (PD) or death from any cause, whichever occurs first.

Spots Global Cancer Trial Database for dna repair gene mutations