Clofarabine and Ara-C for the Treatment of Relapsed AML and Untreated MDS

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to to determine the safety and effectiveness of therapeutic combination - Clofarabine and Cytarabine for the treatment of AML and MDS.

Detailed Description
-----------------
Previous studies of Clofarabine and Cytarabine combination treatment in adult AML and MDS patients showed promising results. This study is done to confirm the findings from previous studies. Primary objective is to determine the overall response rate (complete response [CR] plus partial response [PR]); secondary objective of this study is to characterize and quantify the toxicity profile associated with clofarabine plus cytarabine treatment. A maximum of 35 patients will be treated on this study. They will receive 5 consecutive days of clofarabine intra venous infusion (IVI) followed 4 hours later by cytarabine IVI.Patients will receive up to a maximum of 4 cycles of study treatment. Next cycle will start approximately 4 weeks after Day 1 of previous cycle.No other investigational or commercial agents including chemotherapy, radiotherapy, or immunotherapy may be administered to patients enrolled in this study with the intention of treating the underlying malignancy Patients will remain on study, and be monitored until 4 months have elapsed from the beginning date of their last cycle of treatment.

Official Title
-----------------
Phase II Trial of Clofarabine and Cytarabine in Relapsed Standard-Risk AML and Untreated High-Risk MDS in Adult Patients, and Untreated AML in Selected Elderly Patients at High Risk of Anthracycline Toxicity

Conditions
-----------------
Acute Myelogenous Leukemia, Myelodysplastic Syndromes, Chronic Myelogenous Leukemia

Intervention / Treatment
-----------------
* Drug: Clofarabine and Cytarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Adult patients who are at least 18 years old with histologically confirmed disease as follows: Standard or poor cytogenetic risk acute myelogenous leukemia (AML) according to the Southwestern Oncology Group (SWOG) criteria in first relapse or primary refractory status Untreated high-risk myelodysplastic syndrome (MDS) defined as >10% blasts Chronic myelogenous leukemia (CML) in accelerated phase or blast crisis failing imatinib therapy. Selected elderly patients with untreated AML who are at high risk of anthracycline toxicity. Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or Laboratory values obtained less than or equal to 7 days prior to receiving study treatment: Total bilirubin < 2.0 mg/dL unless elevated due to hemolysis Aspartate transaminase (AST)/alanine transaminase (ALT) less than or equal to 5 × upper limit of normal (ULN) Serum creatinine < 2.0 mg/dL Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment. Exclusion Criteria: Patients with FAB M3 unless relapsed after treatment with ATRA and arsenic trioxide. Patients eligible to receive curative allogeneic transplant as determined by performance status, organ function, availability of a matched donor, etc. Current concomitant chemotherapy, radiation therapy, or immunotherapy. Use of investigational agents within 30 days or any anticancer therapy within 3 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy. Active heart disease including myocardial infarction within the preceding 3 months. History of severe coronary artery disease, arrhythmias other than atrial flutter or fibrillation requiring medication, or uncontrolled congestive heart failure Dyspnea at rest or with minimal exertion. Patients with an active, uncontrolled systemic infection considered to be opportunistic, life-threatening, or clinically significant at the time of treatment or with a known or suspected fungal infection (ie, patients on parenteral antifungal therapy). Pregnant or lactating patients. Prior enrollment in this trial. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clofarabine and Cytarabine<br>Five consecutive days of clofarabine 40 mg/m^2 IVI over 1 hour followed 4 hours later by cytarabine 1000 mg/m^2 IVI over 2 hours | Drug: Clofarabine and Cytarabine<br>* Phase II Trial of Clofarabine and Cytarabine in Relapsed Standard-Risk AML and Untreated High-Risk MDS in Adult Patients, and Untreated AML in selected Elderly Patients at high risk of anthracycline toxicity<br>* Other names: Cytarabine: Ara-C;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete Response [CR] Plus Partial Response [PR]) of Clofarabine Plus Cytarabine in Patients With Relapsed/Refractory AML, Untreated MDS, CML in Blast Phase, or in Selected Untreated Patients With High Risk of Anthracycline Toxicity | Based on International working group for diagnosis, standardization of response criteria, and treatment outcomes for reporting standards for therapeutic trials in Acute myeloid Leukemia: Complete Response (CR) was defined as normalization of marrow blasts (< 5%), recovery of normal heamtopoiesis (absolute neutrophil count >1 X 10^9/l, platelet count ≥100 X10^9/l, and absence of peripheral blood blasts, independent of transfusions and growth factor support. Partial response was defined as blood count recovery as for complete response with the exception of leukemic marrow blasts in the range of 6%-25% or a ≥50% decrease in bone marrow blasts. Treatment failure was defined as a <25% change in marrow blasts within 30 days of starting therapy | Proportion of confirmed responses was estimated by the number of patients who achieved a CR or PR, defined as two consecutive evaluations at least 4 weeks apart, divided by the number of eligible participants in the study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had an Adverse Event While on Treatment With Clofarabine Plus Cytarabine | Patients will be monitored clinically and diagnostically using measures including blood test, bone marrow aspiration and MUGA. Toxicity assessment every week using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be performed. | Up to five months (includes follow up period of 30 days) from the day patient received their first dose of study drug | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, MDS, CML, Relapsed, Refractory, Chemo treatment, Clofarabine, Cytarabine, standard or poor cytogenetic risk AML, untreated high-risk (>10% blasts) MDS, CML in accelerated phase or blast crisis, Elderly AML patients with risk of anthracycline toxicity