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
Condition: Ovarian Cancer; Breast Cancer; Prostate Cancer
MeSH terms: Breast Neoplasms; Prostatic Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Triple Negative Breast Neoplasms
Intervention: LY2606368
Intervention description: 105 mg/m^2 intravenous (IV) once every 14 days of a 28 day cycle
Intervention MeSH terms: Prexasertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 111.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: p53 Dysfunction; Cell Cycle Arrest; Checkpoint Kinases; DNA Damage Repair Pathways; Hereditary Breast and Ovarian Cancer Syndrome

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.
    

Eligibility 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.