Combination Therapy in Cancers With Mutations in DNA Repair Genes

NCT05694715 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 229510NCI-2023-00373
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Solid Tumor; BRCA1 Mutation; BRCA2 Mutation; ATM Gene Mutation; PALB2 Gene Mutation

Keywords

DNA Repair Gene Mutations; Small Molecule Inhibitor; Poly (ADP-ribose) polymerase inhibitor therapy (PARPi)

Outcome Measures

Primary Outcomes (4)

• Percentage of participants with treatment-emergent adverse events

  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

  30 days after the last dose

• Maximum Tolerated Dose (MTD)

  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.

  30 days after the last dose

• Percentage of participants with Dose Limiting Toxicities (DLTs)

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

  30 days after the last dose

• Recommended Phase 2 Dose (RP2D)

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

  Up to 2 years

Secondary Outcomes (4)

• Overall response rate (ORR)

  Up to 2 years

• Duration of overall response (DOR)

  Up to 2 years

• Median duration of stable disease (SD)

  Up to 2 years

• Median Progression-Free Survival (PFS)

  Up to 2 years

Study Arms (6)

Cohort 1 (Niraparib, Irinotecan)

EXPERIMENTAL

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.

Drug: Niraparib; Drug: Irinotecan

Cohort 2 (Niraparib, Irinotecan)

EXPERIMENTAL

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.

Drug: Niraparib; Drug: Irinotecan

Cohort 3a (Niraparib, Irinotecan)

EXPERIMENTAL

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.

Drug: Niraparib; Drug: Irinotecan

Cohort 3b (Niraparib, Irinotecan)

EXPERIMENTAL

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.

Drug: Niraparib; Drug: Irinotecan

Cohort 4a (Niraparib, Irinotecan)

EXPERIMENTAL

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.

Drug: Niraparib; Drug: Irinotecan

Cohort 4b (Niraparib, Irinotecan)

EXPERIMENTAL

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.

Drug: Niraparib; Drug: Irinotecan

Interventions

Niraparib DRUG

Given orally

Also known as: Zejula, Small molecule inhibitor

Cohort 1 (Niraparib, Irinotecan); Cohort 2 (Niraparib, Irinotecan); Cohort 3a (Niraparib, Irinotecan); Cohort 3b (Niraparib, Irinotecan); Cohort 4a (Niraparib, Irinotecan); Cohort 4b (Niraparib, Irinotecan)

Irinotecan DRUG

Given intravenously (IV)

Also known as: Camptosar, Irinotecan hydrochloride, CPT-11

Cohort 1 (Niraparib, Irinotecan); Cohort 2 (Niraparib, Irinotecan); Cohort 3a (Niraparib, Irinotecan); Cohort 3b (Niraparib, Irinotecan); Cohort 4a (Niraparib, Irinotecan); Cohort 4b (Niraparib, Irinotecan)

Eligibility Criteria

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

You may qualify if:

• Individuals 18 years of age or older.
• Ability to understand and willingness to voluntarily sign a written informed consent document prior to any study-related assessments or procedures are conducted; and willing and able to adhere to the study visit schedule and other protocol requirements.
• Solid tumors where topoisomerase I inhibitors have shown efficacy, including gastrointestinal tumors (e.g., colon, pancreatic, gastric cancer and cholangiocarcinoma), breast cancer, and ovarian cancer (prostate cancer is excluded), with one or more of the following DNA repair defects:
• a. BRCA1, BRCA2, ATM, and/or PALB2 (based upon archival tumor tissue or germ line testing from any Clinical Laboratory Improvement Amendments (CLIA) approved lab). This testing must occur prior to study enrollment.
• Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria for response assessment
• Advanced solid tumor malignancy without curative options
• At least 5 half-lives or 3 weeks (whichever is shorter) must have passed since last anticancer therapy
• The washout period for investigational agents without published half-lives should be 3 weeks since last therapy, and all treatment related toxicities must have recovered to less than grade 2.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of \<=1 (Karnofsky \> 60%; Appendix 1).
• Adequate organ function:
• Absolute neutrophil count (ANC) \>= 1.5 X 109/L (no growth factors allowed within 14 days of enrollment)
• Hemoglobin (Hgb) ≥10 g/dL (no transfusion allowed within 7 days of enrollment)
• Platelets (plt) \>= 100 x 109/L
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5 x Upper Limit Normal (ULN), or AST and ALT \<5 x ULN in patients with known liver metastases or known primary liver tumor(s)
• Serum total bilirubin \<= 1.5 x ULN

You may not qualify if:

• Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study at clinician's discretion and not otherwise stated below.
• Prior allergic reaction to PARP inhibitor or irinotecan or their excipients. Prior PARP inhibitor or irinotecan (or topoisomerase 1 inhibitors) use is allowed.
• Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) or suspected sensitivity.
• Individuals with homozygous or compound heterozygous UGT1A1 polymorphisms (e.g., alleles \*28/\*28, \*6/\*6, or \*6/\*28) predicted to be associated with medium-to-high risk of irinotecan-related toxicity
• Individuals receiving any other investigational agents concurrently with the study drugs within 3 weeks or 5 half-lives, whichever is shorter, of the first dose of therapy preceding the study.
• Participants with unstable brain metastases are excluded. Patients with a history of brain metastases (\>1cm) are permitted to enroll if they have been treated and have been stable for a minimum of one month on imaging. Patients may not currently receive steroids for their brain metastases. Patients with small, asymptomatic brain metastases (\<1cm) may enroll.
• Individuals with a second primary malignancy
• Individuals with a prior history of posterior reversible encephalopathy syndrome (PRES)
• Individuals with systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg that has not been adequately treated or controlled
• History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator.
• Known or suspected diagnosis of Myelodysplastic syndromes (MDS) or Acute myeloid leukemia (AML).
• Known Gilbert's disease
• Individuals who are pregnant and/or breast feeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
• Inability to comply with study procedures or unwilling to use adequate highly effective contraception

Sponsors & Collaborators

• University of California, San Francisco: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

niraparib; small molecule inhibitor THX-B; Irinotecan

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Study Officials

• Pamela Munster, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Early Phase Cancer Clinical Trials Recruitment

CONTACT

877-827-3222; EarlyPhaseClinicalTrials@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 12, 2023
• First Posted: January 23, 2023
• Study Start: May 23, 2023
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2028
• Last Updated: March 17, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)