Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if the combination of clofarabine, idarubicin, and cytarabine, or the combination of fludarabine, idarubicin, and cytarabine can help control Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS). The safety of these study drug combinations will also be studied.

Detailed Description
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The Study Drugs: Clofarabine is designed to interfere with the growth and development of cancer cells. Idarubicin is designed to cause breaks in both strands of DNA (the genetic material of cells). This may cause the cancer cells to die. Cytarabine and Fludarabine are designed to insert themselves into the DNA of cancer cells and stop the DNA from repairing itself. Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 4 groups of 6 participants will be enrolled in the Phase I portion of the study. Up to 280 participants will be enrolled in Phase II. Phase I: If you are enrolled in the Phase I portion, the dose of clofarabine you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of clofarabine. Each new group will receive a higher dose of clofarabine than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of clofarabine is found. All participants will receive the same dose level of idarubicin and cytarabine. Phase II: If you are enrolled in the Phase II portion, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups: If you are in Group 1, you will receive clofarabine, idarubicin, and cytarabine. You will receive clofarabine at the highest dose that was tolerated in the Phase I portion. If you are in Group 2, you will receive fludarabine, idarubicin, and cytarabine. Study Drug Administration: Study drug(s) will be given in what are called cycles. Each cycle is 28 days. Phase I: On Days 1-5: You will receive clofarabine by vein over about 1 hour. You will receive cytarabine by vein over about 2 hours. On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes. Phase II (Induction): The first cycle of study drugs is called Induction. If the doctor thinks it is needed, you will have up to 2 Induction cycles. If you are in Group 1: On Days 1-5 of each cycle: You will receive clofarabine by vein over about 1 hour. You will receive cytarabine by vein over about 2 hours. On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes. If you are in Group 2: On Days 1-5 of each cycle: You will receive fludarabine by vein over about 30 minutes. You will receive cytarabine by vein over about 2 hours. On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes. If the doctor thinks it is needed, you may receive less than 5 days of treatment in the induction cycle. If the doctor thinks it is needed, your dose level will be reduced after Induction. Phase II (Consolidation): If the disease responds to the study drugs, you may receive up to 6 more cycles of study drugs. This is called Consolidation. If you are in Group 1: On Days 1-3 of each cycle : You will receive clofarabine by vein over about 1 hour. You will receive cytarabine by vein over about 2 hours. After 1 to 2 hours of receiving cytarabine on Days 1-2 only, you will receive idarubicin by vein over about 30 minutes. If you are in Group 2: On Days 1-3 of each cycle: You will receive fludarabine by vein over about 30 minutes You will receive cytarabine by vein over about 2 hours. After 1 to 2 hours of receiving cytarabine on Days 1-2 only, you will receive idarubicin by vein over about 30 minutes If the cancer does not completely respond after Cycle 1, you may repeat induction (Cycle 1). If the cancer completely responds, you will begin the consolidation cycles. If the doctor thinks it is needed, you may receive less than 3 days of treatment in the consolidation cycles. Study Visits: You will have a physical exam, including measurement of your vital signs before the start of each cycle. Blood (about 2 teaspoons) will be drawn for routine tests every 3-7 days. On Day 28 of every 2-3 cycles (+/- 7 days), if the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease. To collect a bone marrow aspirate, an area of the hip is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. Length of Study: You may continue taking the study drugs for as long as the doctor thinks it is in your best interest or up to 8 total cycles. You will no longer be able to take the study drugs if the disease gets worse or intolerable side effects occur. Your participation on the study will be over once you have completed the long-term follow-up. Long-Term Follow-up: Every 3 months for 1 year after you are off study, you will be called and asked how you are feeling, about any side effects you may be having, and about any other drugs you may be taking. These calls should last about 5 minutes each. This is an investigational study. Cytarabine and Idarubicin are FDA approved and commercially available for the treatment of AML. Fludarabine is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia (CLL). Clofarabine is FDA approved and commercially available for the treatment of acute lymphoblastic leukemia (ALL). The combination of these study drugs is investigational. Up to 292 patients will take part in Phase I and Phase II of this study. All will be enrolled at MD Anderson.

Official Title
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Phase I/II Randomized Study of Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Idarubicin
* Drug: Cytarabine
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign an Institutional Review Board (IRB)-approved informed consent document. Age 18 to 60. Patients above the age of 60 only with principal investigator (PI) approval Diagnosis of newly diagnosed AML [other than acute promyelocytic leukemia (APL)] or high-risk (intermediate-2 or high by International Prostate Symptom Score (IPSS) or > 10% blasts, including CMML) MDS. Prior therapy with hydrea and the use of a single or a two day dose of cytarabine (up to 3 g/m2) for emergency use up to 24 hours prior to start of study therapy is allowed. Prior therapy for MDS or other AHD is not allowed. Eastern Cooperative Oncology Group (ECOG) performance status of </= 3 at study entry. Organ function as defined below (unless due to leukemia): Serum creatinine </= 3 mg/dL Total bilirubin </= 2.5 mg/dL , Alanine aminotransferase (ALT) (SGPT) </= 3 * upper limit of normal (ULN) or </= 5 * ULN if related to disease. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days and must agree to practice acceptable contraceptive methods. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential. Cardiac ejection fraction >/= 40% (by either cardiac echo or multiple gated acquisition scan (MUGA) scan). Documentation of recent (</= 6 months from screening) outside reports is acceptable. Exclusion Criteria: Breast feeding females Patients with uncontrolled active infections (viral, bacterial, and fungal are not eligible). Patients with active secondary malignancy will not be eligible.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clofarabine + Idarubicin + Cytarabine<br>Phase I: Clofarabine Starting dose 15 mg/m2 by vein for 5 days (days 1-5) + Idarubicin 10 mg/m2 by vein on day 1-3 + Cytarabine 1 g/m2 by vein on day 1-5. | Drug: Clofarabine<br>* Phase I: 15 mg/m2 by vein (IV) daily for 5 days of a 28 day cycle. Phase II: Clofarabine (dose selected based on Phase I portion) by vein over approximately 1 hour daily for 5 days (days 1-5) for a 28 day cycle.<br>* Other names: Clolar;Drug: Idarubicin<br>* 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.<br>* Other names: Idamycin;Drug: Cytarabine<br>* 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.<br>* Other names: Cytosine Arabinosine Hydrochloride;Drug: Fludarabine<br>* 30 mg/m2 by vein over approximately 30 minutes daily for 5 days (days 1-5).<br>* Other names: Fludara;|
| Experimental: Group 1 CIA<br>Phase II, Group 1 CIA (Clofarabine + Idarubicin + Cytarabine): Clofarabine Maximum Tolerated Dose (MTD) based on Phase I by vein on days 1-5; Idarubicin 10 mg/m2 by vein on days 1-3; Cytarabine 1 g/m2 by vein on days 1-5. | Drug: Clofarabine<br>* Phase I: 15 mg/m2 by vein (IV) daily for 5 days of a 28 day cycle. Phase II: Clofarabine (dose selected based on Phase I portion) by vein over approximately 1 hour daily for 5 days (days 1-5) for a 28 day cycle.<br>* Other names: Clolar;Drug: Idarubicin<br>* 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.<br>* Other names: Idamycin;Drug: Cytarabine<br>* 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.<br>* Other names: Cytosine Arabinosine Hydrochloride;|
| Experimental: Group 2 FLAI<br>Phase II, Group 2 FLAI (Fludarabine + Idarubicin + Cytarabine): Fludarabine 30 mg/m2 by vein on days 1-5; Idarubicin 10 mg/m2 by vein on days 1-3; Cytarabine 1 g/m2 by vein on days 1-5. | Drug: Idarubicin<br>* 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 1-3) of a 28 day cycle.<br>* Other names: Idamycin;Drug: Cytarabine<br>* 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 1-5) for a 28 day cycle.<br>* Other names: Cytosine Arabinosine Hydrochloride;Drug: Fludarabine<br>* 30 mg/m2 by vein over approximately 30 minutes daily for 5 days (days 1-5).<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Clofarabine, Idarubicin, and Cytarabine | MTD is highest dose level in which <2 patients of 6 develop first cycle dose limiting toxicities (DLT). Toxicity defined as any treatment-related grade 3 or greater non-hematological toxicities. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates of Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) | NCI & Myelodysplastic syndromes (MDS) International Working Group (IWG) Definitions: Complete Response (CR): Neutrophil count ≥1.0 ×10^9/L, Platelet count ≥100 ×10^9/L, Bone marrow aspirate </=5% blasts, No extramedullary leukemia; CRi: Response as in CR but platelets <100 ×10^9/L; Partial response (PR): Neutrophil count ≥ 1.0 ×10^9/L, Platelet count ≥100 ×10^9/L, ≥ 50% reduction in bone marrow blasts over baseline; Clinical benefit: In addition to IWG criteria, in AML, a decrease in bone marrow blasts to <5% is also considered clinical benefit; Stable Disease: In addition to IWG criteria and in absence any of above response criteria, stable disease considered if the bone marrow blast percent does not increase compared to pretreatment level; Relapse: Increase of bone marrow blasts to >10% after initial response. Response assessed Day 28 of every 2-3 cycles during treatment. | 12 months | 
| Event-Free Survival (EFS) at 2 Years | Comparison of the event-free survival (EFS) between treatment CIA and FLAI, where an event is defined to be resistance to treatment, relapse (after response) or death, whichever occurred first. | Up to 2 years or until relapse/death | 
| Overall Survival | Time from date of treatment start until date of death due to any cause or last Follow-up. | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Clofarex, DepoCyt, Acute Myelogenous Leukemia, High-Risk Myelodysplastic Syndrome, MDS, Relapsed, Refractory, Clofarabine, Clolar, Idarubicin, Idamycin, Cytarabine, Ara-C, Cytosar, Cytosine Arabinosine Hydrochloride