Last updated on February 2020

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


Brief description of study

Background
  • All cells go through cycles which allow them to divide. In normal cells, Chk1 and Chk2 (Chk1/2) stop cell division at various points to allow any damage to DNA to be repaired.
  • When Chk1/2 are not present, cells stop dividing and eventually die. LY2606368 blocks the Chk1/2 proteins.
  • Researchers hope that by blocking Chk1/2, it will cause tumor cells to die, thereby shrinking tumors.
    Objective
  • To see if LY2606368 helps shrink tumors in patients with certain breast, ovarian or prostate cancers.
    Eligibility
  • Patients at least 18 years old with breast or ovarian cancer. They must have a mutation in BRCA1/2 genes for group 1, high grade serious ovarian cancer without BRCA1/2 mutation for group 2, or triple negative breast cancer without BRCA1/2 mutation for group 3, or prostate cancer with or without BRCA1/2 mutation for group 4.
    Design
  • Participants will be screened with a medical history and physical exam. They will have blood tests, an electrocardiogram (ECG) heart test, scans, and X-rays. They will have a piece of their tumor removed at entry (CT-assisted biopsy).
  • Study Day 1: Participants will have a physical exam and blood drawn. They may have a CT scan of the chest, abdomen, and pelvis.
  • Day 1 and Day 15 of each 28-day cycle: Participants will receive the study drug through an IV.
  • Vital signs will be checked before and after. An ECG will be done within 1 hour after.
  • Day 15 and Day 28: Participants will have a physical exam, blood drawn, and a 12 lead ECG.
  • Cycle 1: Participants will have weekly phone calls and blood draws. Participants may have another CT-assisted biopsy at the end of cycle 1.
  • Cycle 2 and beyond, blood will be drawn every other week for routine blood tests.
  • Participants will have an after-study visit with a physical exam and blood tests. Participants may have another biopsy when they progressed on treatment. They will have scans of the chest, pelvis, and abdomen and a 12 lead ECG.

Detailed Study 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 ovarian cancer (HGSOC), and triple negative breast cancer (TNBC).
  • Patients 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 patients.
  • We hypothesize that LY2606368 will result in clinical benefit in patients 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 patients.
  • 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
  • Patients 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 patients 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).
  • Patients 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 patients 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 patients. Tumor biopsies will not be performed in Cohort 6.
  • Patients (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.

Clinical Study Identifier: NCT02203513

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