Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation in High Risk AML and Myelodysplastic Syndromes

Study Overview
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Brief Summary
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The study is a Phase II clinical trial. Patients will receive intensity modulated total marrow irradiation (TMI) at a dose of 9 Gy with standard myeloablative fludarabine/ i.v. targeted busulfan (FluBu) conditioning prior to allogeneic hematopoietic stem cell transplant (HSCT).

Detailed Description
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Patients will receive the following conditioning regimen: fludarabine 40 mg/m2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2, IV busulfan targeting a 4800μM/min/ day from day -5 through day -2, and ATG (Thymoglobulin®) at 0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1 (Only for recipients of stem cells from unrelated or mismatched donors). In addition to the above conditioning regimen all patients will receive TMI at a dose of 3Gy on days -3, -2 and -1. On day 0, the stem cell product will be infused according to BMT unit policy. Graft versus host disease (GVHD) prophylaxis will consist of administration of tacrolimus and methotrexate (see Section 8). Post-transplant evaluation will be done as per standard care with study data collected at day 30, 60, 90, 180, 365 and 2 years.

Official Title
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A Phase II Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation in High Risk AML and Myelodysplastic Syndromes

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Busulfan
* Drug: ATG
* Radiation: Total Marrow Irradiation
* Procedure: Stem Cell Product Infusion
* Drug: Tacrolimus
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years Patients with AML or MDS who meet the following criteria: a. Relapsed or refractory AML (including AML in CR2) b. Poor-risk AML in first remission, with remission defined as <5% bone marrow blasts morphologically: AML arising from MDS or a myeloproliferative disorder, or secondary AML Poor risk molecular features including presence of FLT3 internal tandem duplication mutation. Poor-risk cytogenetics: Monosomal karyotype, complex karyotype (> 3 abnormalities), inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7 c. Primary refractory disease d. MDS with at least one of the following poor-risk features: Poor-risk cytogenetics including 3q abnormalities, 7/7q minus or complex cytogenetics (>3 abnormalities) Current or previous INT-2 or high IPSS score Treatment-related MDS MDS diagnosed before age 21 years Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy Life-threatening cytopenias, including those requiring regular PRBC or platelet transfusions e. CML with a history of accelerated or blast phase Patients must have a related or unrelated peripheral blood stem cell donor as follows: Sibling donor must be a 6/6 match for HLA-A, -B at intermediate (or higher) resolution and -DRB1 at high resolution using DNA based typing Unrelated donors must be at least 7/8 match at HLA-A, -B, -C and DRB1 at high resolution using DNA-based typing Exclusion criteria: Presence of significant co morbidity as shown by: Left ventricular ejection fraction < 50% Creatinine clearance <30ml/min Bilirubin > 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST > 5 x ULN FEV1 and FVC < 50% of predicted or DLCO <50% of predicted once corrected for anemia f. Karnofsky score <70 (appendix C) g. Hematopoietic cell transplantation comorbidity index >3 h. Active viral hepatitis or HIV infection j. Cirrhosis Pregnancy Patients unable to sign informed consent Patient who have previously received radiation to >20% of bone marrow containing areas. 4. DONOR ELIGIBILITY AND SELECTION 4.1. Donor Selection Donor evaluation and selection is by standard for normal clinical practice. No study procedures are to be performed on donors. All donors must be willing to donate peripheral blood stem cells and meet institutional or NMDP criteria for donation. The following prioritization will be used when selecting donors: When possible, an HLA compatible sibling will be used as a donor. For patients who do not have an HLA compatible sibling, an unrelated donor will be used 8/8 matched unrelated donors are preferred over single antigen mismatched donors. If more than one potential volunteer unrelated donor is considered suitable further selection of the most suitable donor is at the discretion of the treating physician. The following serves only as a guide for prioritization: Age of donor (18-24 > 25-34 > 35-44 > 45+) Sex and parity 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: 65 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: Patient Treatment<br>Patients will receive fludarabine 40 mg/m2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2, IV busulfan targeting a 4800μM/min/ day from day -5 through day -2, and ATG (Thymoglobulin®) at 0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1 (Only for recipients of stem cells from unrelated or mismatched donors). In addition to the above conditioning regimen all patients will receive TMI at a dose of 3Gy on days -3, -2 and -1. On day 0, the stem cell product will be infused according to BMT unit policy. Graft versus host disease (GVHD) prophylaxis will consist of administration of tacrolimus and methotrexate. Post-transplant evaluation will be done as per standard care with study data collected at day 30, 60, 90, 180, 365 and 2 years. | Drug: Fludarabine<br>* 40 mg/m^2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2<br>* Other names: Fludara®;Drug: Busulfan<br>* targeting a 4800μM/min/ day from day -5 through day -2<br>* Other names: Busulfex®;Drug: ATG<br>* 0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1<br>* Other names: Thymoglobulin®;Radiation: Total Marrow Irradiation<br>* dose of 3Gy on days -3, -2 and -1<br>Procedure: Stem Cell Product Infusion<br>* Day 0 according to BMT unit policy<br>Drug: Tacrolimus<br>* The starting dose is at 0.03 mg/kg/day IV continuous infusion over 24 hr from 4 PM on day -2. Dose will be adjusted to target trough levels of 5-15 ng/mL. More information is available in the protocol document.<br>* Other names: FK-506, Prograf®;Drug: Methotrexate<br>* 5mg/m^2 on Day 1, 5 mg/m^2 on Days 3, 6 and 11<br>* Other names: Trexall®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival of approximately 30% in high-risk patients conditioned with the Fludarabine/ Busulfan regimen | Using a Simon 2 stage optimal design with α of 0.05 and power of 0.8, 15 patients will be enrolled in the first stage. If greater than 5 patients survive to 1 year without relapse the study will continue into stage 2. Recruitment will then continue to a total of 46 patients. In this expanded cohort, if a total of 18 or more patients survive to 1 year without relapse, the treatment will be judged efficacious and worthy of further study. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival | It will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive at 1-year will also be estimated with a 90% exact binomial confidence interval. | Up to 1 year | 
| Overall survival | It will be estimated and reported with 90% confidence intervals. The proportion of patients who are alive at 1-year will also be estimated with a 90% exact binomial confidence interval. | Up to 1 year | 
| Transplant related mortality rate | After accrual of 10 patients, analysis will be performed to ensure that the mortality rate does not exceed 30%. By calculation of confidence intervals to ensure the TRM not exceed 30%, accrual would be halted if n= 6 of 10 (lower bound of the exact, one-sided 90% CI is 35.4%). | Up to 1 year |