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

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 or BRCA2 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, 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 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 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 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
patients 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), 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).

- 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 6 independent cohorts (Cohorts 1-6).

- LY2606368 will be dosed at the RP2D of 105 mg/m2 IV once every 14 days of a 28
day-cycle.

- 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.

- 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 Cohort 1 patients prior to study
enrollment. Patients with documented somatic 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. Patients
with VUS or deleterious mutation in other genes without gBRCA1/2m can be
considered for Cohort 2 or 3 or 5.

2. Patients 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 test.

3. Patients enrolling in the triple negative breast cancer (ER-/PR-/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 NCCN Genetic/Familial
High-Risk Assessment: Breast and Ovarian guideline.

4. For Cohorts 1-3, 5 and 6: 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 Cohort 1.

Patients 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.
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. Patients 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 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.

6. All patients 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 (PR/CR/SD) > 4 months.

7. Patients 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.
Patients 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 RECIST v1.1) but without
biopsiable disease, determined by PI and Interventional Radiology (e.g., cystic
abnormal mass, not safely biopsiable disease). Rising CA125 only is not
considered as platinum-resistant disease. Patients with primary platinum
refractory disease defined as progression during or within 3 months after
receiving first-line platinum based chemotherapy are not eligible.

8. Patients 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. 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. 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. 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 (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.

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 Cohort 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.