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).
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.
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
Sequential
Olaparib
DrugGiven orally
ASTX727
DrugGiven Orally
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.
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.
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.
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.
Objective response rate (ORR) (Phase 2 only)
ORR is defined as the proportion of participants who achieve a best overall response of confirmed complete response (CR) or confirmed partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 comparted to all participants receiving at least 1 dose of the study drug. Complete Response (CR) is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart with any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm (the sum may not be "0" if there are target nodes) and there can be no appearance of new lesions. Partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD with no appearance of new lesions. Proportion and exact 90% confidence intervals will be reported.
Median Duration of overall Response (DoR) (Phase 2 only)
DoR is 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 or progressive disease (PD) is objectively documented. Median time of response with 90% confidence intervals will be summarized using the Kaplan Meier methods.
Median Duration of Stable Disease (SD) (Phase 2 only)
Duration of SD is defined as the duration of time from start of treatment until the date that recurrent or progressive disease (PD) is objectively documented. Median duration of SD with 90% confidence intervals will be summarized using the Kaplan Meier methods.
Median Progression-Free Survival (PFS) (Phase 2 only)
PFS is defined as duration of time from start of treatment to time of disease recurrence, progression (PD) or death from any cause, whichever occurs first. The median PFS and 90% confidence intervals will be reported using Kaplan Meier methods.
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Varun Monga, MBBS
Lead sponsor
University of California, San Francisco
Sponsor institution
National Cancer Institute (NCI)
Collaborator
