Intensity Modulated Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients With Relapsed Hematologic Cancers Undergoing a Second Donor Stem Cell Transplant

Study Overview
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Brief Summary
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This phase I trial studies the side effects and the best dose of intensity modulated total marrow irradiation (IMTMI) when given together with fludarabine phosphate and melphalan in treating patients with cancers of the blood (hematologic) that have returned after a period of improvement (relapsed) undergoing a second donor stem cell transplant. IMTMI is a type of radiation therapy to the bone marrow that may be less toxic and may also reduce the chances of cancer to return. Giving fludarabine phosphate, melphalan, and IMTMI before a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed Description
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PRIMARY OBJECTIVES: I. The determine the maximum tolerated dose (MTD) of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine (fludarabine phosphate)/melphalan as conditioning for second allogeneic stem cell transplantation for patients with hematologic malignancies. SECONDARY OBJECTIVES: I. To determine the overall toxicity and day 100 transplant related mortality after second allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine/melphalan. II. To determine the time to neutrophil and platelet engraftment after second allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine/melphalan. III. To determine the overall survival (OS) and event-free-survival (EFS) in patients with hematologic undergoing second allogeneic hematopoietic stem cell transplant (HSCT) after conditioning with fludarabine/melphalan and IMTMI. OUTLINE: This is a dose-escalation study of IMTMI. CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI twice daily (BID) for 2 to 5 days between days -7 to -3. TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) or bone marrow transplant (BMT) on day 0. GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or orally (PO) BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60. After completion of treatment, patients are followed up periodically for 1 year and then yearly for 2 years.

Official Title
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A Phase I Study of Intensity Modulated Total Marrow Irradiation (IMTMI) in Addition to Fludarabine/Melphalan Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

Conditions
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Previously Treated Myelodysplastic Syndrome, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Hematologic Malignancy

Intervention / Treatment
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* Drug: Fludarabine Phosphate
* Drug: Melphalan
* Radiation: Intensity-Modulated Radiation Therapy
* Radiation: Total Marrow Irradiation
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Procedure: Peripheral Blood Stem Cell Transplantation
* Procedure: Allogeneic Bone Marrow Transplantation
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with the following diseases: acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS) undergoing second allogeneic (allo)-stem cell transplant (SCT) using the same donor or different donor for disease relapse; patients with other hematologic malignancies, including acute lymphoblastic leukemia (ALL), will be at the discretion of the investigators Karnofsky performance status of 70 or above Life expectancy is not severely limited by concomitant illness Adequate cardiac and pulmonary function; patients with decreased left ventricular ejection fraction (LVEF) =< 40% or diffusion capacity of carbon monoxide (DLCO) =< 50% of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this protocol Serum creatinine =<1.5 mg/dL or creatinine clearance > 50 ml/min; some patients with minor deviations may be accepted on protocol after discussion with the principal investigator (PI) Serum bilirubin =< 2.0 mg/dl; some patients with minor deviations may be accepted on protocol after discussion with the PI Serum glutamic oxaloacetic transaminase (SGPT) < 5 x upper limit of normal; some patients with minor deviations may be accepted on protocol after discussion with the PI No evidence of chronic active hepatitis or cirrhosis Human immunodeficiency virus (HIV)-negative Patient is not pregnant Patient or guardian able to sign informed consent DONOR: Since these patients already had first allo-SCT; in the majority time, the same matched donor has been used for second allo-SCT; if the patients have multiple donors, alternative matched (8/8 or 10/10) donor could be used for the second allo-SCT; the donor could be matched related donors or matched unrelated donors from registry DONOR: If more than one potential volunteer unrelated donor is considered suitable, further selection of the most suitable donor will be prioritized as follows or will follow our institutional guideline from our stem cell transplant standard operating procedure (SOP): Age of donor (18-24 > 25-34 > 35-44 > 45+) Sex of donor (male > female, nulliparous female > parous, multiparous female) Cytomegalovirus (CMV) status, if recipient is CMV seronegative (CMV- > CMV+

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (IMTMI, combination chemotherapy, PBSCT or BMT)<br>CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI BID for 2 to 5 days between days -7 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT or BMT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60. | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Melphalan<br>* Given IV<br>* Other names: Alkeran;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMTMI<br>* Other names: Intensity-Modulated Radiotherapy;Radiation: Total Marrow Irradiation<br>* Undergo IMTMI<br>Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: HSCT;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic BMT<br>* Other names: Allogeneic BMT;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: FK 506;Drug: Mycophenolate Mofetil<br>* Given IV or PO<br>* Other names: MMF;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of conditioning regimen defined as any grade III or higher dose-limiting toxicity, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 |  | Up to 30 days post second allo-SCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall incidence of adverse events, graded according to the NCI CTCAE version 4.0 |  | Up to 2 years | 
| Transplant related mortality |  | Day 100 | 
| Time to neutrophil engraftment |  | First day in which the ANC is > 500/mm^3 for 3 consecutive days | 
| Time to platelet engraftment |  | First day the platelet count is > 20,000/mm^3 without transfusion support for 7 consecutive days | 
| overall survival (OS) |  | Up to 2 years | 
| event-free-survival (EFS) |  | Up to 2 years |