Abstract OT-16-01: A phase 1 study of abemaciclib and niraparib as neoadjuvant therapy in hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer
Authors: Li Allen , Naik Arpana , Johnson Nathalie , Goodyear Shaun , Johnson Brett , Park Byung , Corless Christopher , Gray Joe , Mills Gordon , Mitri Zahi 
Published: February 2021

Abstract
Background: Achieving a pathologic complete response (pCR) to neoadjuvant therapy correlates with excellent outcome in early stage breast cancer, including HR+ breast cancer (HRBC). Unfortunately, less than 10% of HRBC patients achieve pCR to neoadjuvant therapy; indicating a need for novel HRBC therapies, especially in the neoadjuvant setting. This study evaluates the novel combination of the cyclin dependent kinase inhibitor (CDKi), abemaciclib, in combination with the poly-ADP ribose polymerase inhibitor (PARPi), niraparib, as a neoadjuvant therapy for HRBC.
Niraparib is an orally bioavailable PARPi indicated for the maintenance treatment of platinum-responsive, ovarian cancer, both 1st line and 2nd line. Abemaciclib is approved as a monotherapy or in combination with endocrine therapy in metastatic HRBC. In addition to targeting CDK4/6, abemaciclib also inhibits CDK1, CDK2, and Aurora A/B kinases, which are involved in DNA damage repair. Targeting kinases with abemaciclib sensitizes tumors to DNA-damaging agents, including PARPi. Preclinical data justifies the combination of abemaciclib and niraparib as a novel combination for the treatment of HRBC.
Trial Design: This is a phase I dose-finding study evaluating the combination of abemaciclib and niraparib as a neoadjuvant therapy in patients with early stage HRBC. All eligible participants with biopsy-proven HRBC will undergo a pre-treatment biopsy and start on-study treatment with the combination of abemaciclib and niraparib using a traditional 3+3 dose-escalation algorithm to determine maximum-tolerated dose (MTD). Dose levels are outlined in Table 1. Each cycle is 28 days. After 2 cycles, participants will undergo repeat imaging and biopsy: those with stable or responding disease will continue to receive an additional 2 cycles of abemaciclib and niraparib, followed by surgical resection. Participants with progressive disease will be switched to standard of care chemotherapy. Once the MTD is determined, additional participants up to a sample size maximum of 25 will be enrolled into an expansion cohort (including those from the dosing finding phase) and treated at the established MTD.
Eligibility Criteria: Key Inclusion Criteria: Age ≥ 18 years, biopsy-proven HR+ Her2 non-amplified breast cancer planned for neoadjuvant chemotherapy, ECOG PS ≤1, disease amenable to curative surgical resection. Key Exclusion Criteria: Evidence of metastatic disease, prior PARPi or CDK 4/6i exposure
Specific Aims: Primary Endpoints: Incidence of dose-limiting toxicities (DLTs), incidence of adverse events (AEs) and serious AEs (per CTCAE 5.0). Secondary Endpoints: overall objective response rate, clinical benefit rate, pCR rate, and rate of residual cancer burden 0-1
Statistical Methods: This phase I dose-escalation study for the proposed combination will follow traditional 3+3 escalation rules. The sample size maximum of 25 (including both those from the dosing finding and expansion portions) allows for a greater than 80% chance that the incidence of any AE as rare as 6.4% or greater will be observed in the cohort. For assessments of preliminary efficacy, the sample size provides a two-sided 95% confidence interval with a half width equal to 0.140 when the targeted pCR is 0.15.
Planned Activation Date: Target Accrual: n=25 participants
Contact: Zahi Mitri, MD, MS 3181 SW Sam Jackson Park Road, OC14HO, Portland, OR 97239 503-494-9160, mitri@ohsu.edu
Table 1. Study Regimen Dose LevelsDose Levels (DLAbemaciclib (PO)Niraparib (PO)DL -1100 mg BID100 mg QDDL 1 starting150 mg BID100 mg QDDL 2150 mg BID200 mg QD
Citation Format: Allen Li, Arpana Naik, Nathalie Johnson, Shaun Goodyear, Brett Johnson, Byung Park, Christopher Corless, Joe Gray, Gordon Mills, Zahi Mitri. A phase 1 study of abemaciclib and niraparib as neoadjuvant therapy in hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-16-01.