Decitabine Followed by Clofarabine, Idarubicin, and Cytarabine in Acute Leukemia

Study Overview
=================
Brief Summary
-----------------
The goal of Phase I of this clinical research study is find the highest tolerable dose of clofarabine that can be given with decitabine, idarubicin, and cytarabine to patients with acute leukemia. The goal of Phase II of this study is to learn if decitabine followed by the combination of clofarabine, idarubicin, and cytarabine can help to control acute leukemia. The safety of this drug combination will also be studied. Decitabine and idarubicin are designed to damage the DNA (the genetic material of cells). This may cause cancer cells to die. Clofarabine is designed to interfere with the growth and development of cancer cells. Cytarabine is designed to insert itself into DNA and stop the DNA from repairing itself.

Detailed Description
-----------------
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 3 groups of 6 participants will be enrolled in the Phase I portion of the study. Up to 74 participants will be enrolled in Phase II. Phase I: If you are enrolled in the Phase I portion, the number of days of clofarabine you receive will depend on when you joined this study. The first group of participants will receive clofarabine for 4 days. Each new group will receive clofarabine for the same number of days, if no intolerable side effects were seen. The number of days may be reduced to 3. The clofarabine dose per day is the same from group to group. All participants will receive the same dose level of decitabine, idarubicin and cytarabine. Phase II: If you are enrolled in the Phase II portion, you will receive decitabine, idarubicin, and cytarabine. You will receive clofarabine for the highest number of days that was tolerated in the Phase I portion. All participants will receive the same dose level of decitabine, idarubicin, cytarabine, and clofarabine. Study Drug Administration: Each study drug cycle is 33 days. The first cycle of study drugs is called Induction. If the doctor thinks it is needed, you will have up to 2 Induction cycles. Phase I (Induction): On Days 1-5 of each cycle, you will receive decitabine 1 time a day by vein over about 1 hour. On Days 6-10 of each cycle: You will receive cytarabine 1 time a day by vein over about 2 hours. On Days 6-8 only, you will receive idarubicin 1 time a day by vein over about 30 minutes. You will receive clofarabine 1 time a day by vein over about 1 hour on Days 6-8 or 6-9, depending on when you join the study. If the doctor thinks it is needed, your dose level will be reduced after Induction. If the doctor thinks it is needed, you may receive fewer days of treatment in the Induction cycle(s). Phase II (Induction): On Days 1-5 of each cycle, you will receive decitabine 1 time a day by vein over about 1 hour. On Days 6-10 of each cycle: You will receive cytarabine 1 time a day by vein over about 2 hours. On Days 6-8 only, you will receive idarubicin 1 time a day by vein over about 30 minutes. You will receive clofarabine 1 time a day by vein over about 1 hour on Days 6-8 or 6-9, depending on the highest number of days clofarabine was tolerated in the Phase I portion of the study. If the doctor thinks it is needed, your dose level will be reduced after Induction. If the doctor thinks it is needed, you may receive fewer days of treatment in the Induction cycle(s). Phases I and II (Consolidation): If the disease responds to the study drugs, you may receive up to 6 more study drug cycles. This is called Consolidation. On Days 1-5 of each cycle: °You will receive decitabine 1 time a day by vein over 1 hour. On Days 6-8 of each cycle: You will receive cytarabine 1 time a day by vein over about 2 hours. You will receive clofarabine 1 time a day by vein over about 1 hour. On Days 6-7 only, you will receive idarubicin 1 time a day by vein over about 30 minutes. If the doctor thinks it is needed, you may receive fewer days of treatment in the Consolidation cycles. Study Visits: Before the start of each cycle, you will have a physical exam, including measurement of your vital signs. Every 3-7 days, blood (about 2 teaspoons) will be drawn for routine tests. On Day 33 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 Treatment: You may continue taking the study drugs for up to 8 cycles. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. 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 your last study drug dose, the study staff will call you and ask 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. Decitabine is FDA approved and commercially available to treat myelodysplastic syndrome (MDS). Clofarabine is FDA approved and commercially available to treat ALL in children. Idarubicin and cytarabine are FDA approved and commercially available to treat AML. The study drug combination is investigational. Up to 92 participants will be enrolled in this study. All will take part at MD Anderson.

Official Title
-----------------
Phase I/II Study of Decitabine (DAC) Followed by Clofarabine, Idarubicin, and Cytarabine (CIA) in Acute Leukemia

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Drug: Decitabine
* Drug: Idarubicin
* Drug: Cytarabine
* Drug: Clofarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sign an IRB-approved informed consent document. Age >/= 18 years and <65 years. Diagnosis of AML [other than acute promyelocytic leukemia] with refractory/relapsed disease (Patients must be primary refractory, in relapse 1, or in relapse 2). NOTE: Patients with AML arising from prior MDS or MPN would be eligible even if they have not received treatment for the AML. NOTE: Patients with relapsed/refractory ALL would also be eligible for the phase II part of the study. NOTE: Use of hydroxyurea and/or up to 4 doses of cytarabine, for emergent cytoreduction is allowed ECOG performance status of </=2 at study entry. Organ function as defined below (unless due to leukemia):Serum creatinine </= 3 mg/dL;Total bilirubin </= 2.5 mg/dL; ALT (SGPT) </= 3 x ULN or </= 5 x ULN if related to disease Cardiac ejection fraction ≥ 40% (by either cardiac ECHO or MUGA scan) Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential. Exclusion Criteria: Breast feeding women Patients with uncontrolled active infections (viral, bacterial, and fungal are not eligible). Patients with active secondary malignancy will not be eligible unless approved by the PI. NOTE: Prior therapy with decitabine, clofarabine, idarubicin, or cytarabine is allowed, unless the prior therapy is identical to the schema/schedule proposed in this study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Starting with Dose level 1, the participants were enrolled by cohort of 3. Once the DLT assessment is completed, another cohort of 3 patients will be enrolled. If at any time, we see more than 30% patients experiencing DLT, we will de-escalate to dose level (-1). Period 1: Dose level 1 Clofarabine 15mg/m^2 daily x 4 days (days 6-9) Period 2: Dose level-1 Clofarabine 15mg/m^2 daily x 3 days (days 6-8)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clofarabine + Cytarabine + Decitabine + Idarubicin<br>Phase I - Decitabine 20 mg/m2 by vein over approximately 1 hour daily for 5 days (days 1-5) Idarubicin 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 6-8) Cytarabine 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 6-10) Phase II - Clofarabine 15 mg/m2 by vein over approximately 1 hour daily (number of days selected based on Phase I portion). Decitabine 20 mg/m2 by vein over approximately 1 hour daily for 5 days (days 1-5) Idarubicin 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 6-8) Cytarabine 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 6-10) | Drug: Decitabine<br>* Phase I and II - 20 mg/m2 by vein daily for 5 days (days 1-5)<br>* Other names: Dacogen;Drug: Idarubicin<br>* Phase I and II - 10 mg/m2 by vein daily for 3 days (days 6-8)<br>* Other names: Idamycin;Drug: Cytarabine<br>* Phase I and II - 1 g/m2 by vein daily for 5 days (days 6-10)<br>* Other names: Cytosine Arabinosine Hydrochloride;Drug: Clofarabine<br>* Phase I Starting Dose - 15 mg/m2 by vein daily for 4 days (days 6-9) Phase II Starting Dose - Maximum tolerated dose from Phase I (number of days selected based on Phase I portion).<br>* Other names: Clolar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Clofarabine | Maximum tolerated dose (MTD) defined as the highest dose schedule in which 6 patients were treated with at most 1 experiencing a dose-limiting toxicity (DLT). Clofarabine 15 mg/m2 IV over approximately 1 hour daily (number of days selected based on Phase I portion). | After second, 33 day cycle | 
| Number of Participants With a Response | Primary endpoint is overall response defined as the best response either complete response, complete remission without platelet recovery, or complete remission without incomplete blood count recovery within 56 days. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Disease-free Survival (DFS). | Time from date of treatment start until the date of first objective documentation of return of disease. | Up to 2 years after participants off study date | 
| Overall Survival | Time from date of treatment start until date of death due to any cause or last Follow-up. | Up to 2 years after participants off study date | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Leukemia, Acute Leukemia, Acute myelogenous leukemia, AML, Acute lymphoblastic leukemia, ALL, Maximum Tolerated Dose, MTD, Response Rate, Decitabine, Dacogen, Idarubicin, Idamycin, Cytarabine, Ara-C, Cytosar, DepoCyt, Cytosine Arabinosine Hydrochloride