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

Recruiting now · Phase 1

Conditions studied: BRCA1 Mutation, BRCA2 Mutation, BRCA Mutation, PALB2 Gene Mutation, Checkpoint Kinase 2 Gene Mutation, ATM Gene Mutation

In brief

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).

Key facts

Study ID: NCT06177171
Run by: Varun Monga, MBBS
People needed: 18
Starts: 2024-02-07
Expected to finish: 2028-01-31
Last updated by the study team: 2026-05-27

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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:
hemoglobin >=10.0 g/dl
absolute neutrophil count >=1,500/microliter (mcL)
platelets >=100,000/mcL
Adequate hepatic function:
total bilirubin ≤ 1.5 x institutional upper limit normal (ULN)
aspartate aminotransferase (AST)/(SGOT) <= 2.5 x institutional ULN
alanine aminotransferase (ALT)/(SGPT) <= 2.5 x institutional ULN
creatinine <= 1.5 x institutional ULN or creatinine clearance Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m\^2, calculated using the Cockcroft-Gault equation.
Ability to understand and the willingness to sign a written informed consent document.
Human immunodeficiency virus (HIV)-infected individuals on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial.

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.

Where it is running

University of California, San Francisco — San Francisco, California, United States (enrolling)

Full record on ClinicalTrials.gov

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