Phase 1 A/B Study of LY2606368 in Combination with Cytarabine and Fludarabine in Patients with Relapsed/Refractory Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HRMDS)
The goal of this clinical research study is to study the safety of LY2606368 when given in combination with fludarabine and cytarabine. The effectiveness of the study drug combination when given to patients with relapsed or refractory AML or HRMDS will also be studied.
Disease Group: Leukemia
Treatment Agent: Cytarabine,Fludarabine,LY2606368
Treatment Location: Only at MDACC
Sponsor: Eli Lilly and Company
Primary objective: To determine the safety and toxicity profile of combination therapy of LY2606368, fludarabine and cytarabine in patients with relapsed or refractory (first or second salvage) AML or HRMDS. Secondary objectives: To determine the: complete response (CR), CR with incomplete count recovery (CRi), morphologic leukemia free state (MLFS) and partial response (PR) rates duration of response disease-free survival and overall survival with combination therapy of LY2606368, fludarabine and cytarabine in patients with relapsed or refractory AML/HRMDS Correlative studies including but not limited to total and phosphor H2AX, Chk1, Chk2, Cdc25, Rb, CDK, Akt in AML cells by flow cytometry and/or Western blot.
IRB Review and Approval Date: 05/04/2016
Recruitment Status: Open
Projected Accrual: N/A
1) All patients with histologically or cytologically confirmed relapsed
or refractory acute myeloid leukemia (AML) [except acute promyelocytic
leukemia] or relapsed or refractory high-risk myelodysplastic syndrome
(HRMDS) (Int-2 or higher risk by IPSS); patients with chronic
myelomonocytic leukemia (CMML) can be enrolled if they can be classified
as HRMDS using MDS criteria. Patients should not have received more than
one salvage therapy. Second induction regimen or stem cell transplant in
remission will be considered salvage therapy. Refractory subjects, up to
second consecutive salvage.
2) Patients must be 18 years or older.
3) Patients must have a performance status of 0-2 (ECOG scale).
4) Patients must have adequate renal function (serum creatinine less than or equal to 1.3 mg/dL and/or creatinine clearance > 40 mL/min).
5) Patients must have adequate hepatic function (bilirubin less than or equal to 1.5 mg/dl (unless due to Gilbert’s syndrome); SGOT/AST or SGPT/ALT less than or equal to 2.5 X the upper limit of normal (ULN) for the reference lab.
6) Patients must have normal cardiac ejection fraction (LVEF >/= 45%).
7) QTc interval </= 470 msecs, no familial history of QTc prolongation or ventricular arrhythmias.
8) Female patients must not be pregnant or lactating. Female patients of childbearing potential (including those <1 year post-menopausal) and male patients must agree to use contraception.
9) Patients who have received prior stem cell transplantation will be allowed to enroll as long as prior transplantation has been at least 3 months before enrollment in the trial and any transplant related toxicities have subsided to Grade 1 or less.
1) Patients must not have untreated or uncontrolled life-threatening infection.
2) Patients must not have been treated with CHK1/2 inhibitors.
3) Patients must not have received chemotherapy and/or radiation therapy within 2 weeks of start of protocol treatment. Hydroxyurea is allowed up to 48 hours prior to starting therapy in the setting of rapidly proliferating disease.
4) Patients must not have received an investigational anti-cancer drug within two weeks of start of protocol treatment.
5) Patients must not have active central nervous system leukemia. Patients with history of CNS leukemia with no evidence of active CNS disease may be enrolled. Maintenance intrathecal chemotherapy for adequately treated CNS involvement with leukemia is allowed with approval from the study supporter.
6) Patients must not have significant cardiac co-morbidity including: History of acute coronary syndromes (including myocardial infarction and unstable angina) within 12 months; coronary angioplasty or stenting within 6 months; history or evidence of current >/= Class III congestive heart failure as defined by the New York Heart Association (NYHA); patients with intra-cardiac defibrillators or permanent pacemakers
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