Guadecitabine With or Without Idarubicin or Cladribine in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This randomized phase II trial studies how well guadecitabine with or without idarubicin or cladribine works in treating older patients with previously untreated acute myeloid leukemia. Guadecitabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether guadecitabine with or without idarubicin or cladribine is more effective in treating older patients with previously untreated acute myeloid leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the complete remission (CR) rate, remission duration, leukemia-free survival, and survival in patients >= 70 years with previously untreated acute myeloid leukemia (AML) with 4 different guadecitabine (SGI-110) single agent and SGI-110 based combination regimens. II. To determine the safety profile and tolerability of the 4 SGI-110 single agent and SGI-110 based combination regimens in patients >= 70 years of age with previously untreated AML. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: INDUCTION THERAPY: Patients receive guadecitabine subcutaneously (SC) on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CR with incomplete platelet recovery (CRp) continue on to Maintenance therapy; patients not achieving CR or complete remission with incomplete hematologic recovery (CRi) but deriving clinical benefit may continue to Maintenance therapy at the discretion of the Principal Investigator (PI). MAINTENANCE THERAPY: Patients receive guadecitabine as in Induction therapy. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. ARM II (CLOSED): INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-10. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 (days 1-10 of courses 1 and 2). Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. ARM III: INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin intravenously (IV) over up to 1 hour on days 1-2. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin IV over up to 1 hour on day 1. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. ARM IV (CLOSED): INDUCTION THERAPY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every month.

Official Title
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Four-Arm Randomized Phase II Study of SGI-110: 5 Days, Versus 10 Days, Versus 5 Days + Idarubicin, Versus 5 Days + Cladribine, in Previously Untreated Patients &gt;/= 70 Years With Acute Myeloid Leukemia

Conditions
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Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cladribine
* Drug: Guadecitabine
* Drug: Idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated AML patients, except those who have received prior therapy with hydroxyurea, single agent chemotherapy (e.g. decitabine), hematopoietic growth factors, biological or targeted therapies are allowed Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Sign a written informed consent form Total bilirubin =< 2 mg/dL Serum glutamate pyruvate transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) =< 4 x upper limit of normal (ULN) Creatinine clearance of >= 50 mL/min (estimated by the Cockcroft-Gault [C-G] formula) Male patients must use an effective contraceptive method during the study and for a minimum of 8 weeks after study treatment Baseline left ventricular ejection fraction (LVEF) >= 40% Exclusion Criteria: Patients with >= New York Heart Association (NYHA) grade 3 heart disease as assessed by history and/or physical examination Patients who received more than one full course of prior hypomethylating agents azacitidine or decitabine Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) Pregnant or lactating patients Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results Any concurrent malignancy with the exception of the following: a) patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; b) patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (guadecitabine)<br>INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine as in Induction therapy. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Guadecitabine<br>* Given SC<br>* Other names: SGI-110;|
| Experimental: Arm II (CLOSED) (guadecitabine)<br>INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-10. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 (days 1-10 of courses 1 and 2). Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Guadecitabine<br>* Given SC<br>* Other names: SGI-110;|
| Experimental: Arm III (guadecitabine, idarubicin)<br>INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin IV over up to 1 hour on days 1-2. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin IV over up to 1 hour on day 1. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Guadecitabine<br>* Given SC<br>* Other names: SGI-110;Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;|
| Experimental: Arm IV (CLOSED) (guadecitabine, cladribine)<br>INDUCTION THERPAY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI. MAINTENANCE THERAPY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Cladribine<br>* Given IV<br>* Other names: RWJ-26251;Drug: Guadecitabine<br>* Given SC<br>* Other names: SGI-110;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Complete Response | Complete Response = Complete Remission (CR) + Complete Remission without blood count recovery (CRi) - CR: Neutrophil count >/= 1.0 x 10^9/L and platelet count >/= 100 x 10^9/L, and normal bone marrow differential (</+ 5% blasts). (CRi): Peripheral blood and bonemarrow results as for CR, but with platelet counts of < 100 x 109/L or ANC < 1.0 x 109/L | Up to 4 years, 3 months | 
| Remission Duration | The date of Complete Response to the date of loss of response or last follow-up. | Up to 4 years, 3 months | 
| Leukemia-free Survival | Survival time will be estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to assess the differences of time to events between groups. Time from date of treatment start until the date of first objective documentation of disease-relapse. | Up to 4 years, 3 months | 
| Survival | Survival time will be estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to assess the differences of time to events between groups. | Up to 4 years, 3 months | 
| Number of Participants With the Most Frequently Reports Grade 3 or 4 Adverse Event. | The most frequently reported adverse events will be determined by the Principal Investigator. The number of participants who experienced the most frequent grade 3 or 4 adverse events will be reported. | Up to 4 years, 3 months |