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Breast Diseases

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Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive abemaciclib PO BID and niraparib PO QD. Treatment repeats every 28 days for up to 2-4 cycles in the absence of disease progression or unacceptable toxicity. Patients who complete 4 cycles undergo standard of care mastectomy or lumpectomy. Patients demonstrating progressive disease after only 2 cycles are switched to receive standard of care chemotherapy prior to undergoing mastectomy or lumpectomy.

Abemaciclib

Niraparib Tosylate Monohydrate

Alexandra Zimmer, M.D.

This phase I trial tests the side effects and best dose of abemaciclib and niraparib in treating patients with breast cancer that is positive for estrogen or progesterone receptors (hormone receptor positive \[HR+\]) and HER2 negative. Abemaciclib may stop the growth of tumor cells by blocking certain proteins called cyclin-dependent kinases, which are needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as niraparib, can keep PARP from working so tumor cells can't repair themselves and grow. Giving abemaciclib and niraparib together before surgery may make the tumor smaller.

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of the combination of abemaciclib and niraparib tosylate monohydrate (niraparib).

II. To assess safety and tolerability of the combination of abemaciclib and niraparib in early stage HR+ breast cancer.

SECONDARY OBJECTIVES:

I. To determine clinical response to treatment. II. To determine pathologic response to treatment. III. To determine feasibility of combination as determined by no delay to standard of care breast surgery.

EXPLORATORY OBJECTIVE:

I. To assess occurrence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) malignancy.

OUTLINE: This is a phase 1 dose-escalation study of abemaciclib in combination with niraparib followed by a dose-expansion study.

Patients receive abemaciclib orally (PO) twice daily (BID) and niraparib PO once daily (QD). Treatment repeats every 28 days for up to 2-4 cycles in the absence of disease progression or unacceptable toxicity. Patients who complete 4 cycles undergo standard of care mastectomy or lumpectomy. Patients demonstrating progressive disease after only 2 cycles are switched to receive standard of care chemotherapy prior to undergoing mastectomy or lumpectomy.

Patients are followed up at 30 days after date of surgery, every 3 months for the first 6 months, every 6 months for 2 years, then annually for up to 5 years from date of surgery.

Abemaciclib and Niraparib Before Surgery for the Treatment of Hormone Receptor Positive HER2 Negative Breast Cancer

A Phase 1 Study of Abemaciclib and Niraparib as Neoadjuvant Therapy in Hormone Receptor Positive (HR+) HER2 Negative (HER2-) Breast Cancer

Dose-limiting toxicities will specifically be reported for the DLT evaluation period using the MTD-evaluable population.

Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA version 21.1) preferred term and system organ class and a preferred term. The severity of the AEs will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Descriptive statistics using the safety evaluable population will be used to report on all on-study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, serious adverse events (SAEs), treatment-related SAEs, and AEs leading to discontinuation per CTCAE v5.0. Grade 3-4 laboratory abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria.

Overall response will be summarized descriptively. ORR will be estimated with 95% confidence interval (CI). The CI will be calculated based on the exact method for binomial distributions.

An estimate of CBR will be measured and reported with 95% exact CI. Participants who achieve a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months on the current protocol will be qualified as deriving benefit from therapy and will count towards the CBR measurement.

pCR will be tabulated as proportions and analyzed descriptively. Rate of delay to breast surgery will be summarized descriptively

RCB will be tabulated as proportions and analyzed descriptively. Rate of delay to breast surgery will be summarized descriptively

Defined as proportion of participants with time-to-surgery \> 90 days following completion of study therapy due to study-treatment related toxicity.

Spots Global Cancer Trial Database for her2 negative breast adenocarcinoma