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
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|ClinicalTrials.gov Identifier: NCT02203513|
Recruitment Status : Recruiting
First Posted : July 30, 2014
Last Update Posted : September 28, 2018
- 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.
- To see if LY2606368 helps shrink tumors in patients with certain breast, ovarian or prostate cancers.
- 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.
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Ovarian Cancer Breast Cancer Prostate Cancer||Drug: LY2606368||Phase 2|
- 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.
- 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.
- 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.
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||153 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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, and High Grade Serous Ovarian Cancer|
|Study Start Date :||July 29, 2014|
|Estimated Primary Completion Date :||June 28, 2019|
|Estimated Study Completion Date :||June 30, 2020|
Prexasertib monotherapy treatment
105 mg/m^2 IV once every 14 days of a 28 day cycle
- Objective response rate (CR+PR) [ Time Frame: every 2 cycles for Groups 1-3 and every 3 cycles for Group 4 ]Objective response rate (CR+PR) of single agent LY2606368 in patients with gBRCAm-associated breast and ovarian cancers, HGSOC and TNBC at low genetic risk.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02203513
|Contact: Nicole D. Houston, R.N.||(240) firstname.lastname@example.org|
|Contact: Jung-Min Lee, M.D.||(240) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937|
|Principal Investigator:||Jung-Min Lee, M.D.||National Cancer Institute (NCI)|