Antineoplastic Agents

All Drugs and Chemicals

Olaparib

Decitabine

Decitabine and cedazuridine drug combination

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Antimetabolites

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.

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.

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.

ASTX727

Early Phase Cancer Clinical Trials

Pamela Munster, MD

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).

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of olaparib and ASTX7272 in patients with advanced solid tumors and germline or somatic mutations in the homologous recombination repair (HRR) pathway.

II. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for olaparib and ASTX7272 in patients with advanced solid tumors and germline or somatic mutations in the HRR pathway.

SECONDARY OBJECTIVES:

I. To evaluate the preliminary efficacy of the recommended dose level of olaparib and ASTX727 in patients with solid tumor malignancies and germline or somatic mutations in the HRR pathway.

EXPLORATORY OBJECTIVES:

I. To characterize HRD mutations in tumor samples and assess functional impact on HRR.

II. To assess cell free deoxyribonucleic acid (cfDNA) as a predictive biomarker of response and resistance.

III. To create patient-derived xenograft (PDX) and patient-derived organoid (PDO) models for sensitive and resistant tumors from patients treated with olaparib and ASTX727.

OUTLINE:

Testing for DNA repair mutations should occur prior to study consent or prior to enrollment via a Clinical Laboratory Improvement Amendments of 1988 (CLIA)-approved test. This study uses a 3+3 design. In phase 1, participants will be assigned to the starting dose. If no DLTs are found in the first cycle for the first 3 participants, an additional cohort at the next dose level will open for enrollment. In phase 1b, participants will receive the recommended phase 2 dose (RP2D). Participants will be followed for approximately 30 days after discontinuation of study treatment for safety, and every 16 weeks for up to 2 years.

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

A Phase I/Ib Study of Olaparib and ASTX727 in BRCA1/2- and HRD-mutated Tumors

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.

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.

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.

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.

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.

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.

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.

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.

Spots Global Cancer Trial Database for checkpoint kinase 2 gene mutation