A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer

Summary

Participation Requirements

Description

Background: Checkpoint kinases 1 and 2 (Chk1/2) are major regulators of the cell cycle and are intimately associated with the cellular response to DNA damage and repair. Chk1/2 also function as the primary mediators of cell cycle arrest in tumors with p53 dysfunction, such as high-grade serous ovari...

Background: Checkpoint kinases 1 and 2 (Chk1/2) are major regulators of the cell cycle and are intimately associated with the cellular response to DNA damage and repair. Chk1/2 also function as the primary mediators of cell cycle arrest in tumors with p53 dysfunction, such as high-grade serous ovarian cancer (HGSOC), and triple negative breast cancer (TNBC). Participants with germline BRCA1 or BRCA2 mutation have inherent defects in DNA damage repair pathways. Chk1/2 inhibition alone yielded DNA damage and mitotic catastrophe preclinically, even in the absence of DNA damage by external agents in tumors with underlying DNA repair dysfunction. The second-generation Chk1/2 inhibitor, LY2606368, yielded safety and preliminary single agent activity in advanced cancer participants. We hypothesize that LY2606368 will result in clinical benefit in participants with gBRCAm-associated breast or ovarian cancers, and HGSOC and TNBC with low genetic risk. Objectives: To determine the objective response rate (CR+PR) of single agent LY2606368 in patients with gBRCAm-associated breast or ovarian cancer, HGSOC and TNBC with low genetic risk. To determine the safety and toxicity, and progression-free interval (PFI) of LY2606368 in pretreated participants. To determine biochemical changes in the DNA damage repair and cell cycle check point pathways in tumor and blood samples in response to treatment. To determine potential resistance mechanisms to LY2606368 treatment in HGSOC. Eligibility: Participants with recurrent/refractory BRCA mutant breast or ovarian cancer, HGSOC, and TNBC, for whom there remains no standard curative measures. A documented deleterious germline or somatic BRCA mutation for breast or ovarian cancer participants enrolling in Cohort 1. Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for HGSOC (Cohort 2). Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for TNBC (Cohort 3). Effective with amendment I (version date 4/24/2017), mCRPC, Cohort 4 was closed. Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC with measurable and biopsiable disease (Cohort 5). Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC with measurable but without biopsiable disease (Cohort 6). Participants must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. ECOG performance status 0-2 and adequate organ and marrow function. Design: This is an open label, single arm phase II trial to examine activity of LY2606368 in participants in the 6 independent cohorts (Cohorts 1-6). LY2606368 will be dosed at the RP2D of 105 mg/m2 IV once every 14 days of a 28 day-cycle. Research samples including whole blood, CTCs, and tumor biopsies will be obtained for PD endpoints at baseline, Cycle 1 Day 15 (6-24hr post-2nd dose), and/or at progression in all participants. Tumor biopsies will not be performed in Cohort 6. Participants (Cohorts 1-3, 5 and 6) will be evaluated every two cycles for response using RECIST v1.1 and every cycle for safety using CTCAE v4.0.

Tracking Information