| Eligibility |
- 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.
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