Study of Stem Cell Transplantation for Hematologic Malignancies Using Clofarabine and Busulfan Regimen

Study Overview
=================
Brief Summary
-----------------
The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with Busulfan as a full-intensity conditioning (Clo/BU4 regimen) prior to transplant and then (Phase II) to investigate the safety and effectiveness of this regimen as a conditioning for stem cell transplant in the treatment of aggressive hematologic malignancies in subjects where more conventional approaches are failing.

Detailed Description
-----------------
Transplants with stem cells collected from the blood of an unrelated donor (allo-HSCT) are being used more commonly for many blood cancers which are not curable with more conventional methods of chemotherapy. Although allo-HSCT has great potential, there are still high risks due to infections, graft-versus-host disease (GVHD), where the donor's cells attack the recipient's tissues as foreign, and due to toxic effects of the chemotherapy drugs given to prepare (or condition) the recipient's bone marrow for transplant. As a reduced intensity conditioning, a combination of Fludarabine and a lower dose of Busulfan (Flu/BU2) is one of the most popular regimens. Among full-intensity regimens, a combination of Fludarabine and standard-dose Busulfan (Flu/BU4) has been investigated recently and shown to be very well tolerated. Clofarabine, similar to Fludarabine, is known to have a stronger anti-tumor effect than Fludarabine and has shown promise in treating aggressive acute leukemias. In addition, evidence is that it is well-tolerated with manageable side effects especially in older subjects. Thus replacing Fludarabine with Clofarabine in a full-intensity transplant regimen, Clo/BU4 may provide a regimen with increased anti-tumor activity without adding significant risks of toxicity. The goals of the study are (Phase I) to determine the appropriate dose for Clofarabine with Busulfan as a full-intensity regimen (Clo/BU4) and then (Phase II) to investigate the safety and effectiveness of this regimen as a conditioning for HSCT in the treatment for aggressive hematologic malignancies, in subjects where more conventional approaches are failing.

Official Title
-----------------
Phase I/II Study of Myeloablative Allogeneic Stem Cell Transplantation for Aggressive Hematologic Malignancies Using Clofarabine and Busulfan x 4 (Clo/BU4) Regimen

Conditions
-----------------
Leukemia, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome

Intervention / Treatment
-----------------
* Drug: Clofarabine/Busulfan x 4
* Procedure: Peripheral blood stem cell transplant
* Radiation: Total Lymphoid Irradiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Disease Criteria Acute leukemia or chronic myelogenous leukemia in blastic crisis or accelerated phase, not in remission at the time of transplant Myelodysplastic syndrome, with more than 5% blasts in bone marrow at the time of transplant Hodgkin and Non-Hodgkin Lymphomas: Not in CR in PET scan or CT scan before transplant, or relapsed within 1 year from previous remission CLL not in remission Multiple Myeloma, not in remission Suitable donor available (related or unrelated) Age, Organ Function Criteria Age: ≤ 70 years Cardiac: LV Ejection Fraction ≥ 40% by MUGA or Echocardiogram Pulmonary: FEV1 and FVC ≥ 40% predicted, and DLCO (corrected for hemoglobin) ≥ 40% of predicted Renal: Adult population: 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) Renal: Pediatric population: serum creatinine clearance ≥ 90 ml/min/1.73 m2 as calculated by the Schwartz formula for estimated GFR Hepatic: serum total bilirubin ≤ 2.0 mg/dl and AST / ALT ≤ ULN x 4 Performance status: Karnofsky ≥ 70% Exclusion Criteria: Other active life-threatening cancer requiring treatment other than allo-HSCT HIV1 or HIV2 positive Uncontrolled medical or psychiatric disorder Uncontrolled viral or fungal infection Active CNS leukemia Non-compliant to medications No appropriate caregivers identified

Ages Eligible for Study
-----------------
Maximum Age: 70 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: Clo/BU4<br>Study will start at the 2nd dose level of three Clofarabine levels, in combination with Busulfan. The Clofarabine level that each subsequent patient is treated at is determined by a method using continual reassessment. After pre-conditioning, subjects will receive a peripheral blood stem cell transplant. | Drug: Clofarabine/Busulfan x 4<br>* Clofarabine IV (dose levels) 1st dose level: 20 mg/m2/day x 5 days 2nd dose level: 30 mg/m2/day x 5 days 3rd dose level: 40 mg/m2/day x 5 days Busulfan IV 3.2 mg/kg daily x 4 days<br>Procedure: Peripheral blood stem cell transplant<br>* Peripheral blood stem cell transplant, after pre-conditioning drug treatment<br>Radiation: Total Lymphoid Irradiation<br>* Total Lymphoid Irradiation (TLI) of 4 Gy, if cord blood transplant<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regimen Related Toxicities | The incidence of non-hematological toxicities (Common Terminology Criteria for Adverse Events (CTCAE) 3.0) from initiation of conditioning to Day + 30 or toxicities after day +30, possibly, probably or definitely related to conditioning for all patients treated with Clofarabine (independent of dose level). | two years | 
| One-year Overall Survival Rate for AML | Percent Overall Survival (OS) for at one year for subjects with Acute Myeloid Leukemia (AML). | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-year Overall Survival for All Cases. | Percent Overall Survival (OS) at two years for all patients. | 2 years | 
| Five Year Overall Survival for All Cases | The number of patients alive at 5 years | five years |