Clofarabine, Cytarabine, and Thymoglobulin for Allogeneic Transplantation

Study Overview
=================
Brief Summary
-----------------
This study will test the combination of clofarabine, cytarabine, and thymoglobulin as a non-myeloablative conditioning regimen for patients with myelodysplastic syndromes or acute myeloid leukemia undergoing allogeneic stem cell transplant.

Detailed Description
-----------------
Current reduced intensity conditioning regimens have been able to decrease TRM (treatment related mortality) but suffer from increased rates of disease relapse. Disease burden at transplantation, as measured by percent myeloblasts, predicts relapse. Current regimens employ fludarabine and busulfan with various adjutants, but these agents are not part of the usual armamentarium used versus leukemia and have questionable anti-leukemic activity. By substituting clofarabine and cytarabine, a combination with proven anti-leukemic activity in the relapsed and refractory setting as well as activity versus MDS, as the back bone of the regimen we hope overcome residual disease and improve post-transplant relapse rates. Furthermore the principal toxicity of this regimen is myelosuppression, which should be abrogated by the infusion of stem cells. Thymoglobulin is included due to its minimal contribution to toxicity but significant benefits in engraftment, and controlling acute and chronic GVHD, which are major contributors to TRM and disease specific activity in MDS.

Official Title
-----------------
A Non-Myeloablative Conditioning Regimen for Allogeneic Transplantation With Clofarabine, Cytarabine, and Thymoglobulin for Myelodysplastic Syndrome and Acute Myeloid Leukemia

Conditions
-----------------
Myelodysplastic Syndromes, Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Clofarabine
* Drug: Cytarabine
* Drug: Thymoglobulin
* Procedure: Stem cell infusion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (Patient): Myelodysplastic Syndrome (MDS), as defined by the World Health Organization criteria, OR Chronic Myelomonocytic Leukemia (CMML) as defined by the French American British classification OR Acute Myeloid Leukemia (AML) in complete remission [excluding FAB-M3] diagnosed by standard criteria and meet the criteria below: Patients may be in any CR No more than 2 cycles of consolidation. Any consolidation regimen may be used. No more than 6 months from documented CR to transplant. Age 18 years or older. ECOG performance status <=2 Identification of suitable donor DLCO >=40% with no symptomatic pulmonary disease LVEF by MUGA >= 30% Serum creatinine <=1.0 mg/dL; if serum creatinine >1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black). Bilirubin <=2 times the upper limit of normal AST <=3 times the upper limit of normal Donor criteria: HLA-Matched Sibling: The donor must be an adequate HLA match as determined by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1) as defined by institutional standards. Matched Unrelated Donor: An acceptable match per NMDP standards based on high resolution molecular typing. The donor must be healthy and must be an acceptable donor as per institutional standards for stem cell collection. The donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease. There is no upper age restriction for donors, but they must be at least 18 years of age. Syngeneic donors are not eligible. No known HIV. Exclusion Criteria: Pregnant or nursing. Active systemic infection considered opportunistic, life threatening or clinically significant at the time of treatment. Severe concurrent disease, including severe insulin-dependent diabetes, uncontrolled hypertension, transient ischemic attacks, uncontrolled symptomatic coronary artery disease, or symptomatic CNS involvement or psychiatric illness/social situations that would limit compliance with study requirements. Known HIV disease. History of other malignancy except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast unless the subject has been off treatment and free from disease for > 3 years. Active disease at the time of transplant.

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Arm 1: Non-myeloablative conditioning regimen<br>Clofarabine 40mg/m2/day IV over two hours daily x 5 days on Days -6 thru -2 Cytarabine 1gm/m2/day IV over two hours daily x 5 days on Days -6 thru -2 after the START of Clofarabine. Thymoglobulin 1.0mg/kg IV over 6 hours X 1 day on Day -4, then 2.5mg/kg/day x 2 days on Days -3 and -2. Stem Cell Transplant - On day 0 a minimum of total CD34+ cell dose of 2 x10E6/kg (actual weight of recipient) will be infused. | Drug: Clofarabine<br> <br> * Other names: Clolar;Drug: Cytarabine<br> <br> * Other names: Cytosar;Drug: Thymoglobulin<br> <br> * Other names: Anti-thymocyte globulin;Procedure: Stem cell infusion<br> <br> * Other names: Bone marrow transplant;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-month Treatment Related Mortality |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Specific Response Rates | Disease-specific partial response and complete response. | One, three, six and twelve months. | 
| Engraftment as Measured by Percent Donor Chimerism |  | Day +30 | 
| Engraftment as Measured by Percent Donor Chimerism |  | Day +40-+60 | 
| Engraftment as Measured by Percent Donor Chimerism |  | Day +80-+90 | 
| Overall Survival |  | 5 years from time of restaging | 
| Disease-free Survival | Disease-free survival is defined as the length of time after treatment ends that the participant survives without any signs or symptoms of that cancer. | 5 years from time of restaging | 
| Rate of Acute Graft-versus-host Disease (GVHD) | Acute GVHD occurs within 100 days of transplant. | Up to 100 days after transplant | 
| Rate of Chronic Graft-versus-host Disease (GVHD) |  | 100 days-1 year after transplant | 
| Use Conventional STR-PCR Method for Monitoring Engraftment | Includes assessment of mixed chimerism in the whole blood, myeloid cells, T cells, and B cells. | Up to 1 year after transplant | 
| Median Time to Progression | Time to progression is defined as the length of time from the start of treatment until the disease starts to get worse or spread to other parts of the body. | 5 years from time of restaging | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Conditioning regimens, Stem Cell Transplantation, Hematopoietic Stem Cell Transplantation, Allogeneic Stem Cell Transplantation, Nonmyeloablative conditioning, Clofarabine, Cytarabine, Anti-thymocyte globulin