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

• ClinicalTrials.gov Identifier: NCT02203513
• Recruitment Status: Terminated
• First Posted: July 30, 2014
• Results First Posted: September 10, 2022
• Last Update Posted: September 10, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Jung-Min Lee, M.D., National Cancer Institute (NCI)

Study Description

Brief Summary:

Background:

• All cells go through cycles which allow them to divide. In normal cells, checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) (CHEK 2 (Chk1/2) stop cell division at various points to allow any damage to deoxyribonucleic acid (DNA) to be repaired.
• When Chk1/2 are not present, cells stop dividing and eventually die. Chk1/2 Inhibitor (Prexasertib (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:

- Participants at least 18 years old with breast or ovarian cancer. They must have a mutation in BRCA1 BReast CAncer gene 1 and BRCA2 BReast CAncer gene 2 (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 (computed tomography (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 intravenous (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

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 deoxyribonucleic acid (DNA) damage and repair. Chk1/2 also function as the primary mediators of cell cycle arrest in tumors with tumor protein P53 (p53) dysfunction, such as high-grade serous ovarian cancer (HGSOC), and triple negative breast cancer (TNBC).
• Participants with germline BRCA1 BReast CAncer gene 1 and BRCA2 BReast CAncer gene 2 (BRCA1/2) 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 (Prexasertib (LY2606368) yielded safety and preliminary single agent activity in advanced cancer participants.
• We hypothesize that LY2606368 will result in clinical benefit in participants with Germline BRCA-Mutated (gBRCAm)-associated breast or ovarian cancers, and HGSOC and TNBC with low genetic risk.

Objectives:

• To determine the objective response rate (Complete Response (CR)+Partial Response (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 BReast CAncer gene (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), Metastatic Castration-Resistant Prostate Cancer (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.
• Eastern Cooperative Oncology Group (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 recommended phase 2 dose (RP2D) of 105 mg/m^2 intravenous (IV) once every 14 days of a 28 day-cycle.
• Research samples including whole blood, circulating tumor cells (CTCs), and tumor biopsies will be obtained for pharmacodynamics (PD) endpoints at baseline, Cycle 1 Day 15 (6-24hour (hr) 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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and every cycle for safety using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 111 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 20, 2015
• Actual Primary Completion Date: August 27, 2021
• Actual Study Completion Date: August 27, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1-Prexasertib; Prexasertib (LY2606368) monotherapy treatment	Drug: LY2606368; 105 mg/m^2 intravenous (IV) once every 14 days of a 28 day cycle; Other Name: Prexasertib

Outcome Measures

Primary Outcome Measures :

1. Objective Response (Complete Response (CR) + Partial Response (PR) [ Time Frame: Cohorts 1-3, 5, & 6 were restaged every 2 mos. Cohort 4 was restaged every 3 mos. Restaging continued until participant's disease was deemed progressive by RECIST or until removed from treatment for other etiology for an combined average of 133 days. ]
   Objective response (CR+PR) of single agent Prexasertib (LY2606368) in participants with germline BReast CAncer gene -Mutated (gBRCAm)-associated breast and ovarian cancers, high grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) at low genetic risk. Response was measured using the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of diameters of target lesions.

Other Outcome Measures:

1. Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). [ Time Frame: Participants were followed for the duration of treatment and up to 4 weeks after being off treatment, an average of 7 months ]
   Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:

  1. A documented deleterious germline breast cancer 1 and breast cancer 2 mutation (gBRCA1/2m) obtained in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, including but not limited to Myriad Genetics, either by multi-gene panels or individual testing, for Cohort 1 participants prior to study enrollment. Participants with documented somatic BReast CAncer gene (BRCA) mutation obtained in a CLIA-certified laboratory also will be considered for Cohort 1. Variants of uncertain significance (VUS) of BRCA1/2 are not considered deleterious. Participants with variant of uncertain significance (VUS) or deleterious mutation in other genes without gBRCA1/2m can be considered for Cohort 2 or 3 or 5.
  2. Participants enrolling in the sporadic high grade serous epithelial or high grade endometrioid ovarian cancer group, Cohort 2, must have a negative family history of hereditary breast ovarian cancer (HBOC) syndrome, or negative gBRCA1/2m mutation test.
  3. Participants enrolling in the triple negative breast cancer (estrogen receptor (ER)-/progesterone receptor (PR)-/human epidermal growth factor receptor 2 (Her2)-) group, Cohort 3, must have a negative family history of HBOC syndrome, or negative gBRCA1/2m test. A family history of HBOC is defined by National Comprehensive Cancer Network® (NCCN®) Genetic/Familial High-Risk Assessment: Breast and Ovarian guideline.

  4. For Cohorts 1-3, 5 and 6: participants must have breast and/or epithelial or endometrioid ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer histologically or cytologically confirmed at the National Cancer Institute (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. Participants with gBRCA1/2m with history of or active breast and ovarian cancers are considered for Cohort 1.

     Participants enrolling in Cohort 5, the recurrent platinum-resistant sporadic high grade serous epithelial or high grade endometrioid ovarian cancer group, must have a negative family history of HBOC syndrome, or negative gBRCA1/2m test. Participants should have recurrent platinum-resistant - defined as disease recurrence by imaging within 6 months of the last receipt of platinum-based chemotherapy. Rising mucin 16 (CA125) only is not considered as platinum-resistant disease. Participants with primary platinum refractory disease defined as progression during or within 3 months after receiving first-line platinum-based chemotherapy are not eligible.

  5. All participants 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 non-nodal 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 computed tomography (CT) scan.
  6. All participants except Cohort 6 must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy. For Cohort 5, the second biopsy at progression is mandatory for the responders (Partial Response (PR)/Complete Response (CR)/Stable Disease (SD) > 4 months.
  7. Participants enrolling in Cohort 6, the recurrent platinum-resistant sporadic high grade serous epithelial or high grade endometrioid ovarian cancer group, must have a negative family history of HBOC syndrome, or negative gBRCA1/2m test. Participants should have recurrent platinum-resistant, defined as disease recurrence by imaging within 6 months of the last receipt of platinum-based chemotherapy. This cohort should have measurable (defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1) but without biopsiable disease, determined by principal investigator (PI) and Interventional Radiology (e.g., cystic abnormal mass, not safely biopsiable disease). Rising CA125 only is not considered as platinum-resistant disease. Participants with primary platinum refractory disease defined as progression during or within 3 months after receiving first-line platinum-based chemotherapy are not eligible.
  8. Participants must be at least 4 weeks from previous therapy (chemotherapy, hormonal therapy, and radiation therapy, or investigational agents; 6 weeks for mitomycin C).
  9. The use of raloxifene, denosumab, or bisphosphonates for bone health is allowed.
  10. There is no limit on the number of prior therapies.
  11. Participants must be at least 1 week from the last dose of complementary or alternative medications.
  12. Participants who have had major surgery must be fully recovered and greater than or equal to 4 weeks postoperative prior to enrolling on study.
  13. Age greater than or equal to 18 years.
  14. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

  15. Participants 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 or equal to 10mg/dL

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

      Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT) less than or equal to 3 X institutional upper limit of normal

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

      OR

      measured creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for participants with

      creatinine levels above institutional normal.

  16. Potassium (K) should be within the range of greater than or equal to 3.6 mEq/L.
  17. Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the start of the study.
  18. The effects of Chk1/2 Inhibitor (Prexasertib LY2606368) on the developing human fetus are unknown. For this reason, all subjects of reproductive potential must agree to use adequate contraception prior to study entry, for the duration of study participation, and for at least four months following the last dose of experimental therapy. All subjects of reproductive potential must also agree to use both a barrier method and a second method of birth control during the course of the study and for four months after the last dose of study drug(s). Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
  19. Ability of subject to understand, adhere to protocol requirements and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Participants who are receiving any other investigational agents.
2. Participants 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. Participants with brain metastases diagnosed greater than 1 year prior to study entry may be considered if they received sterilizing therapy to the central nervous system (CNS) (resection or radiation) and have been CNS recurrence-free for the 1-year period.
3. Participants who have had prior treatment with LY2606368 or other Chk inhibitors
4. Participants 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. Participants who have corrected QT interval (QTc) interval of > 470 msec on a screening electrocardiogram.
6. Participants 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 (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE); except alopecia). Electrolyte abnormalities that are corrected with supplementation will be eligible. Participants 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 principal investigator (PI).
8. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically significant gastrointestinal (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. Participants 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. Participants with gBRCA1/2m and primary breast or ovarian cancers will be eligible for Cohort 1.
11. Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LY2606368. HIV- positive participants who are not on highly active antiretroviral therapy (HAART) and have cluster of differentiation 4 (CD4) counts > 500 will be considered on an individual basis.

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jung-Min Lee, M.D.; National Cancer Institute (NCI)

  Study Documents (Full-Text)

Documents provided by Jung-Min Lee, M.D., National Cancer Institute (NCI):

Study Protocol and Statistical Analysis Plan  [PDF] December 2, 2020

Informed Consent Form: Standard Consent  [PDF] April 2, 2019

Informed Consent Form: Cohort: All Participants Consent  [PDF] March 30, 2021

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jin T, Xu L, Wang P, Hu X, Zhang R, Wu Z, Du W, Kan W, Li K, Wang C, Zhou Y, Li J, Liu T. Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile. J Med Chem. 2021 Oct 28;64(20):15069-15090. doi: 10.1021/acs.jmedchem.1c00994. Epub 2021 Oct 19.

Lee JM, Nair J, Zimmer A, Lipkowitz S, Annunziata CM, Merino MJ, Swisher EM, Harrell MI, Trepel JB, Lee MJ, Bagheri MH, Botesteanu DA, Steinberg SM, Minasian L, Ekwede I, Kohn EC. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study. Lancet Oncol. 2018 Feb;19(2):207-215. doi: 10.1016/S1470-2045(18)30009-3. Epub 2018 Jan 18.

• Responsible Party: Jung-Min Lee, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02203513
• Other Study ID Numbers: 140156; 14-C-0156
• First Posted: July 30, 2014
• Results First Posted: September 10, 2022
• Last Update Posted: September 10, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

For All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

In addition, all large-scale genomic sequencing data will be shared with subscribers to database of Genotypes and Phenotypes (dbGaP).

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol genomic data sharing plan (GDS) for as long as database is active.

Access Criteria

Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jung-Min Lee, M.D., National Cancer Institute (NCI):

p53 Dysfunction; Cell Cycle Arrest; Checkpoint Kinases; DNA Damage Repair Pathways; Hereditary Breast and Ovarian Cancer Syndrome

Additional relevant MeSH terms:

Breast Neoplasms; Prostatic Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Neoplasms, Female; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Prexasertib; Protein Kinase Inhibitors