Chk1/2 Inhibitor (LY2606368) in Women With BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Non-High Risk Triple Negative Breast Cancer, and High Grade Serous Ovarian Cancer at Low Genetic Risk

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02203513
First received: July 29, 2014
Last updated: August 20, 2014
Last verified: July 2014
  Purpose

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 women with certain breast or ovarian cancers.

Eligibility:

- Women 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.

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....

Condition Intervention Phase
Ovarian Cancer
Breast Cancer
Drug: LY2606368
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in Women With BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Non-High Risk Triple Negative Breast Cancer, and High Grade Serous Ovarian Cancer at Low Genetic Risk.

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 [ Time Frame: every 2 cycles ] [ Designated as safety issue: No ]

Estimated Enrollment: 78
Study Start Date: July 2014
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Women with gBRCA massociated breast or ovarian cancer
Drug: LY2606368
105 mg/m2 IV once every 14 days of a 28 day cycle
Experimental: 2
HGSOC at low genetic risk
Drug: LY2606368
105 mg/m2 IV once every 14 days of a 28 day cycle
Experimental: 3
TNBC at low genetic risk
Drug: LY2606368
105 mg/m2 IV once every 14 days of a 28 day cycle

Detailed 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 BRCA1/2 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 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 women with gBRCAm-associated breast or ovarian cancer, and HGSOC and TNBC with low genetic risk.
  • To determine the safety and toxicity, and PFI of LY2606368 in pretreated women.
  • To determine biochemical changes in the DNA damage repair and cell cycle check point pathways in tumor and blood samples in response to treatment.

Eligibility:

  • Women 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 Group 1.
  • Negative gBRCAm testing or negative family history of hereditary breast and ovarian cancer syndrome for HGSOC (Group2).
  • Negative gBRCAm testing or negative family history of hereditary breast and ovarian cancer syndrome for TNBC (Group 3).
  • 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 3 independent cohorts (Groups 1-3).
  • 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 at progression in all patients.
  • Patients will be evaluated every two cycles for response using RECISTv1.1 criteria and every cycle for safety using CTCAEv4.0.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. A documented deleterious germline BRCA1/2 mutation (gBRCA1/2m) obtained in a CLIA-certified laboratory, including but not limited to Myriad Genetics, either by multi-gene panels or individual testing, for Group 1 patients prior to study enrollment. Variants of uncertain significance (VUS) of BRCA1/2 are not considered deleterious. Patients with VUS or deleterious mutation in other genes without gBRCA1/2m can be considered for group 2 or 3.
    2. Patients enrolling in the sporadic high grade serous epithelial ovarian cancer group, Group 2, must have a negative family history of hereditary breast ovarian cancer (HBOC) syndrome, or negative gBRCA1/2m test.
    3. Patients enrolling in the triple negative breast cancer (ER-/PR-/Her2-) group, Group 3, must have a negative family history of HBOC syndrome, or negative gBRCA1/2m test. A family history of HBOC is defined by NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian guideline.
    4. Patients must have breast and/or epithelial ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer histologically or cytologically confirmed at the NCI that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. ER/PR/HER2 status needs to be documented either by an outside source or at NCI. Patients with gBRCA1/2m with history of or active breast and ovarian cancers are considered for Group 1.
    5. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.
    6. All patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
    7. Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal therapy, and radiation therapy, or investigational agents; 6 weeks for mitomycin C). The use of raloxifene for bone health is allowed.
    8. There is no limit on the number of prior therapies.
    9. Patients must be at least 1 week from the last dose of complementary or alternative medications.
    10. Patients who have had major surgery must be fully recovered and greater than or equal to 4 weeks postoperative prior to enrolling on study.
    11. Women age greater than or equal to 18 years.
    12. ECOG performance status less than or equal to 2.
    13. Patients must have normal organ and marrow function (in the absence of transfusion 24 hours prior to dosing) as defined below:

      leukocytes greater than or equal to 3,000/mcL

      absolute neutrophil count greater than or equal to 1,500/mcL

      platelets greater than or equal to 100,000/mcL

      hemoglobin greater than 10mg/dL

      total bilirubin less than or equal to 1.5 times institutional upper limit of normal

      AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal

      creatinine less than or equal to 1.5 times institutional upper limit of normal

      OR

      measured creatinine clearance greater than or equal to 45 mL/min/1.73 m(2 )for patients with creatinine levels above institutional normal.

    14. Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the start of the study.
    15. The effects of LY2606368 on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for at least three months following the last dose of experimental therapy. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
    16. Ability of subject to understand, adhere to protocol requirements and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  1. Patients who are receiving any other investigational agents.
  2. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastases diagnosed greater than 1 year prior to study entry may be considered if they received sterilizing therapy to the CNS (resection or radiation) and have been CNS recurrence-free for the 1-year period.
  3. Patients who have had prior treatment with LY2606368 or other Chk inhibitors
  4. Patients with a serious cardiac condition, such as congestive heart failure; New York Heart Association Class III/IV heart disease; unstable angina pectoris; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant despite medical intervention; or arrhythmias that are symptomatic or refractory to medical intervention.
  5. Patients who have QTc interval of > 470 msec on a screening electrocardiogram.
  6. Patients with a prior history of drug-induced serotonin syndrome, or a family history of long-QT syndrome.
  7. Lack of recovery of prior adverse events due to prior cancer therapy to Grade less than or equal to 1 (NCICTCAE; except alopecia). Electrolyte abnormalities that are corrected with supplementation will be eligible. Patients with platinum-related grade 2 or greater hypomagnesemia (on replacement) will be eligible. Stable persistent grade 2 peripheral neuropathy may be allowed as determined on a case-by-case basis at the discretion of the PI.
  8. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically significant GI bleeding or hemoptysis within 28 days prior to the start of the study, or psychiatric illness/social situations that would limit compliance with study requirements.
  9. Patients with active infection will not be eligible, but may become eligible once infection has resolved and they are at least 7 days from completion of antibiotics.
  10. Another previous or current invasive malignancy within the last 2 years, with the exception of curatively treated stage Ia cervical carcinoma, or resected stage Ia endometrial cancer, and noninvasive nonmelanoma skin cancers. Patients with gBRCA1/2m and primary breast or ovarian cancers will be eligible for Group 1.
  11. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LY2606368. HIV- positive patients who are not on HAART and have CD4 counts > 500 will be considered on an individual basis.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02203513

Contacts
Contact: Nicole D. Houston, R.N. (301) 443-6431 houstonnd@mail.nih.gov
Contact: Jung-Min Lee, M.D. (301) 443-7735 leej6@mail.nih.gov

Locations
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 Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Jung-Min Lee, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
No publications provided

Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT02203513     History of Changes
Other Study ID Numbers: 140156, 14-C-0156
Study First Received: July 29, 2014
Last Updated: August 20, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
p53 Dysfunction
Cell Cycle Arrest
Checkpoint Kinases
DNA Damage Repair Pathways
Hereditary Breast and Ovarian Cancer Syndrome

Additional relevant MeSH terms:
Breast Neoplasms
Ovarian Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders

ClinicalTrials.gov processed this record on September 18, 2014