Olaparib and ASTX727 in BRCA1/2- and Homologous Recombination Deficient (HRD)-Mutated Tumors

NCT06177171 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 239925R01CA255613-02NCI-2023-10542
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single center, phase I/Ib clinical trial evaluating the combination of the poly adenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib with the DNA methyltransferase (DNMT) inhibitor ASTX727, which is an oral formulation of decitabine with cedazuridine (a cytidine deaminase inhibitor that allows for oral administration). The study population consists of adults with advanced/metastatic solid tumor malignancies with germline or somatic mutations in the HRR pathway (i.e., BReast CAncer gene 1 (BRCA1), BReast CAncer gene 2(BRCA2), Partner And Localizer of BRCA2 (PALB2), ATM, and/or Checkpoint kinase 2 (CHEK2) mutations).

Conditions

Checkpoint Kinase 2 Gene Mutation; BRCA1 Mutation; BRCA2 Mutation; BRCA Mutation; PALB2 Gene Mutation; ATM Gene Mutation

Keywords

Homologous Recombination Deficiency; HRR Pathway

Outcome Measures

Primary Outcomes (4)

• Proportion of participants with treatment-emergent Adverse Events (AEs) (Phase 1 Only)

  Adverse events will be classified and graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 and reported by dose level.

  Up to 2 years

• Percentages of dose-limiting toxicities (DLTs) (Phase 1 Only)

  A dose-limiting toxicity (DLT) is defined as any of the following events that are considered by the investigator to be at least possibly related to olaparib or ASTX727 and are observed during cycle 1. The percentage of participants with DLTs will be reported.

  Up to 1 cycle (1 cycle is 28 days)

• Maximum Tolerated Dose (MTD) (Phase 1 Only)

  The MTD is defined as the highest dose at which no more than one instance of dose-limiting toxicity (DLT) is observed among the first 6 participants treated.

  Up to 1 cycle (1 cycle is 28 days)

• Recommended Phase 2 Dose (RP2D) (Phase 1 Only)

  The RP2D for a planned Phase 2 trial will be selected based on the evaluation of dose-limiting toxicities and adverse events measured using CTCAE v5.0.

  Up to 1 cycle (1 cycle is 28 days)

Secondary Outcomes (4)

• Objective response rate (ORR) (Phase 2 only)

  Up to 2 years

• Median Duration of overall Response (DoR) (Phase 2 only)

  Up to 2 years

• Median Duration of Stable Disease (SD) (Phase 2 only)

  Up to 2 years

• Median Progression-Free Survival (PFS) (Phase 2 only)

  Up to 2 years

Study Arms (3)

Phase 1: Olaparib, ASTX727 (D1,D3)-Starting Dose

EXPERIMENTAL

Participants enrolled in the starting dose cohort will receive 300 mg Olaparib orally, twice a day (BID) on day 1 and day 14 for each 28-day cycle. Participants will also receive 35/100mg ASTX727 on days 1, and 3 of the 28-day cycle. Participants may continue study treatment indefinitely until disease progression unacceptable toxicity, withdrawal, or study closure; whichever comes first. If no DLTs are reported for the first 3 participants, an additional dose escalation cohort may open at the next dose level.

Drug: Olaparib; Drug: ASTX727

Phase 1: Olaparib + ASTX727 (D1,D3,D5)

EXPERIMENTAL

If no DLTs are reported in the previous dose level, participants enrolled in this cohort will receive 300 mg olaparib orally, twice a day (BID) on day 1 and day 14 for each 28-day cycle. Participants will also receive 35/100mg ASTX727 on days 1, 3 and 5 of the 28-day cycle. Participants may continue study treatment indefinitely until disease progression unacceptable toxicity, withdrawal, or study closure; whichever comes first.

Drug: Olaparib; Drug: ASTX727

Phase 1b: RP2D (Olaparib, ASTX727) - Dose Expansion

EXPERIMENTAL

Participants enrolled in this cohort will receive the RP2D based on the safety and efficacy profile determined in the Phase 1 cohorts. Participants will receive the RP2D dose of olaparib orally, twice a day (BID) on day 1 and day 14 for each 28-day cycle. Participants will also receive 35/100mg ASTX727 at the RP2D for the 28-day cycle. Participants may continue study treatment indefinitely until disease progression unacceptable toxicity, withdrawal, or study closure; whichever comes first.

Drug: Olaparib; Drug: ASTX727

Interventions

Olaparib DRUG

Given orally

Also known as: LYNPARZA

Phase 1: Olaparib + ASTX727 (D1,D3,D5); Phase 1: Olaparib, ASTX727 (D1,D3)-Starting Dose; Phase 1b: RP2D (Olaparib, ASTX727) - Dose Expansion

ASTX727 DRUG

Given Orally

Also known as: INQOVI, C-DEC

Phase 1: Olaparib + ASTX727 (D1,D3,D5); Phase 1: Olaparib, ASTX727 (D1,D3)-Starting Dose; Phase 1b: RP2D (Olaparib, ASTX727) - Dose Expansion

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically or cytologically confirmed advanced solid tumors (any solid tumor type) with:
• Phase I, Dose Escalation: Germline and/or somatic mutation\* in one or more of the following genes: BRCA1, BRCA2, PALB2, ATM, and/or CHEK2.
• Phase Ib, Dose Expansion\*\*:
• Expansion Cohort A (n=6): Germline mutation\* (with or without accompanying somatic mutation) in one or more of the following genes: BRCA1, BRCA2, PALB2, ATM, and/or CHEK2;
• Expansion Cohort B (n=6): Germline and/or somatic mutation\* in one or more of the following genes: BRCA1, BRCA2, PALB2, ATM, and/or CHEK2.
• Testing for DNA repair mutations should occur prior to study consent or enrollment via a CLIA-approved test.
• Has measurable disease per RECIST 1.1 as assessed by the investigator. Lesions situated in previously irradiated areas are considered measurable if progression has been demonstrated in such lesions.
• Participants may have received any lines of prior therapy and is refractory or intolerant to therapy approved for their condition or unwilling to receive currently approved therapy.
• Prior PARP inhibitors are allowed, provided the following two criteria are met:
• Participant has NOT required toxicity related dose reductions or dose delays during prior PARP inhibitor treatment; and
• Participant has NOT experienced any allergic reaction to PARP inhibitors.
• Age \>=18 years
• Eastern Cooperative Oncology Group (ECOG) performance status \<2, or Karnofsky \>60%
• Demonstrates adequate organ function as defined below:
• Adequate bone marrow function:

You may not qualify if:

• Has received systemic anticancer therapies within 3 weeks of first dose, radiation within 2 weeks, antibody therapy within 4 weeks. Concomitant administration of Luteinizing hormone-releasing hormone (LHRH) analogues for prostate cancer and somatostatin analogues for neuroendocrine tumors are allowed as per standard of care.
• Has not recovered from adverse events due to prior anti-cancer therapy to \<= grade 1 (CTCAE v5.0) or baseline (other than alopecia).
• Receipt of any other investigational agents or devices within 3 weeks prior to initiation of trial therapy.
• Unable to swallow oral medications
• Individuals who are breast-feeding/chest-feeding (because of the potential for serious adverse reactions in breastfeed infants from olaparib and ASTX727). Study participants who are lactating must agree to discontinue breast-feeding/chest-feeding for the duration of study treatment and for 1 month after the final dose of trial therapy.
• Individuals who are pregnant (because of the potential for olaparib and ASTX727 to cause serious adverse reactions to the unborn child). Females of childbearing potential (defined below) must have a negative urine or serum pregnancy test within 72 hours prior to first administration of study drug. A female is considered to be of childbearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice), unless it is documented that the individual meets either of the following two criteria: (1) has reached a postmenopausal state (\>= 12 continuous months of amenorrhea with no identified cause other than menopause); or (2) has undergone surgical sterilization (i.e., hysterectomy and/or bilateral oophorectomy for removal of uterus and/or ovaries). Individuals with any condition or social circumstance that, in the opinion of the investigator, would impair the participant's ability to comply with study activities, interfere with participant safety, or study endpoints.
• Diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Taking a prohibited medication that cannot be safely discontinued or substituted.

Sponsors & Collaborators

• Pamela Munster: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

MeSH Terms

Interventions

olaparib; decitabine and cedazuridine drug combination

Study Officials

• Pamela Munster, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Early Phase Cancer Clinical Trials

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: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 11, 2023
• First Posted: December 20, 2023
• Study Start: February 7, 2024
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2028
• Last Updated: February 2, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)