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 : February 6, 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 BRCA1/2 mutations (gBRCAm) 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 gBRCAmassociated 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.
- Patients with recurrent/refractory gBRCAm-associated breast or ovarian cancer, HGSOC, and TNBC, for whom there remains no standard curative measures.
- A documented deleterious gBRCA1/2m for breast or ovarian cancer patients enrolling in Cohort 1.
- Negative gBRCAm testing or negative family history of hereditary breast and ovarian cancer syndrome for HGSOC (Cohort 2).
- Negative gBRCAm 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
- Negative gBRCAm 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 gBRCAm 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 I patients in the 5 independent cohorts (Cohorts 1-6).
- LY2606368 will be dosed at the RP2D of 105 mg/m2 IV once every 14 days of a 28daycycle.
- 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 4, 2018|
|Estimated Study Completion Date :||June 3, 2019|
Prexasertib monotherapy treatment
105 mg/m^2 IV once every 14 days of a 28 day cycle
- To determine the objective response rate (CR+PR) of single agent LY2606368, a second-generation Chk 1/2 inhibitor, in women with gBRCAm-associated breast and ovarian cancers, and HGSOC and TNBC at low genetic risk and mCRPC [ Time Frame: Every 2 cycles for Groups 1-3, 5 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.
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)|