Patient case: 72-year-old male with Cholangiocarcinoma. Genetic variant: BRCA2. Other conditions: Diabetes.

Clinical trial: 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

Summary: 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 patients with certain breast, ovarian or prostate cancers.
  Eligibility:
  - 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.
  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.

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.
  -  Emerging data suggest half of patients with metastatic castrate-resistant prostate cancer (mCRPC) have p53 mutation and subsets of mCRPC have dysfunction in genes involved 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, and subsets of mCRPC.
  Objectives:
  -  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, and mCRPC.
  -  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.
  Eligibility:
  -  Patients with recurrent/refractory gBRCAm-associated breast or ovarian cancer, HGSOC, TNBC, and mCRPC, 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).
  -  mCRPC with soft tissue disease amenable to biopsy (Group 4). Bone only disease is not eligible.
  -  Negative gBRCAm testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC (Group 5).
  -  Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. For patients with mCPRC (Group 4), patients may be on hormonal therapy with GnRH agonists/antagonists.
  -  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 I patients in the 5 independent cohorts (Groups 1-5).
  -  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.
  -  Patients (groups 1-3 and 5) will be evaluated every two cycles for response using RECIST v1.1 and every cycle for safety using CTCAE v4.0.
  -  Patients with mCRPC (group 4) will be evaluated every three cycles for response using RECIST v1.1 criteria as per the prostate cancer clinical trials working group criteria 2 (PCWG2). Evaluation will include CT imaging and technetium 99 bone scan at baseline and every 3 cycles.

Eligibility: -or 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 or 5.
  2. Patients enrolling in the sporadic high grade serous epithelial or high grade endometrioid 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. For Groups 1-3 and 5: patients must have breast and/or epithelial or endometrioid 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 enrolling in the recurrent platinum-resistant sporadic high grade serous epithelial or high grade endometrioid ovarian cancer group, Group 5, must have a negative family history of HBOC syndrome, or negative gBRCA1/2m test. Patients should have recurrent platinum-resistant - defined as disease recurrence by imaging within 6 months of the last receipt of platinum-based chemotherapy. Rising CA125 only is not considered as platinum-resistant disease.
  6. For Group 4: patients must have metastatic, progressive, castrate resistant prostate cancer (CRPC) with soft tissue disease that is amenable to biopsy.
  -  Histopathological confirmation of prostate cancer by the Laboratory of Pathology of the NCI or Pathology Department of the Walter Reed National Military Medical Center is required prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled if the patient has a clinical course that is consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. All efforts should be made to have the material forwarded to the research team for use in correlative studies in cases where original tissue blocks or archival biopsy material is available.
  -  Patients must have metastatic soft tissue disease that is amenable to biopsy. Amenable bone biopsy may also be obtained (in addition to soft-tissue biopsy) if indicated.
  -  Patients must have received at least one month of prior treatment with enzalutamide and/or abiraterone.
  -  Patients must have castrate levels of testosterone (<50 ng/dl [1.74 nmol/l]).
  -  Patients must have undergone bilateral surgical castration or must agree to continue on GnRH agonists/antagonists for the duration of the study.
  -  Patients with metastatic castrate resistant prostate cancer (mCRPC) will be enrolled in Group 4, independent of gBRCA1/2m status. gBRCA1/2m testing report will be requested if done.
  7. 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 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 CT scan.
  8. All patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy. For Group 5, the second biopsy at progression is mandatory for the responders (PR/CR/SD) > 4 months. Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal therapy, and radiation therapy, or investigational agents; 6 weeks for mitomycin C). For patients with mCPRC (Group 4), patients may be on hormonal therapy with GnRH agonists/antagonists.
  9. The use of raloxifene, denosumab, or bisphosphonates for bone health is allowed. Patients may be on prednisone for control of symptoms related to prostate cancer.
  10. There is no limit on the number of prior therapies.
  11. Patients must be at least 1 week from the last dose of complementary or alternative medications.
  12. Patients 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. ECOG performance status less than or equal to 2.
  15. 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 or equal to 10mg/dL
  total bilirubin less than or equal to 1.5 X institutional upper limit of normal
  AST(SGOT)/ALT(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 m2 for patients 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 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. Sexually active male subjects and their female partners must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for four months after the last dose of study drug(s), even if oral contraceptives are also used. 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 or her male partner 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. Patients who are receiving any other investigational agents.
  2. Special considerations for Group 4 mCRPC cohort:
  - Prior treatment with enzalutamide must be discontinued at least 28 days before the first dose of study treatment in order to participate in this study. Prior treatment with abiraterone must be discontinued at least 14 days before the first dose of study treatment. Subjects with prostate cancer currently receiving GnRH agonists/antagonists must agree to continue these agents.
  3. The subject has received radiation therapy:
  -  to bone or brain metastasis within 14 days before the first dose of study treatment
  -  to any other site(s) within 28 days before the first dose of study treatment
  4. The subject has received radionuclide treatment within 6 weeks prior to the first dose of the study treatment
  5. The subject has had treatment with docetaxel for the treatment of metastatic castrate sensitive prostate cancer within 6 months before the first dose of study treatment.
  6. The subject has had progression of prostate cancer during 6 cycles of prior docetaxel treatment for castrate sensitive disease.
  7. 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.
  8. Patients who have had prior treatment with LY2606368 or other Chk inhibitors
  9. 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.
  10. Patients who have QTc interval of > 470 msec on a screening electrocardiogram.
  11. Patients with a prior history of drug-induced serotonin syndrome, or a family history of long-QT syndrome.
  12. Lack of recovery of prior adverse events due to prior cancer therapy to Grade less than or equal to 1 (NCI CTCAE; 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.

Relevance to patient case: definitely relevant