BMT-06: Study of Intensity Modulated Total Marrow Irradiation (IM-TMI)

Study Overview
=================
Brief Summary
-----------------
Pre-transplant conditioning will include targeted total marrow irradiation (TMI) at a dose of 6Gy. Graft-versus-host disease prophylaxis will include cyclophosphamide 50 mg/kg on Day +3 and 4 along with tacrolimus and mycophenolate mofetil

Detailed Description
-----------------
This is a single arm phase II clinical trial. Patients will receive a standard conditioning regimen with fludarabine, cyclophosphamide and total body irradiation (Flu/Cy/TBI) prior to haploidentical hematopoietic stem cell transplant (HSCT). In addition the pre-transplant conditioning will include targeted total marrow irradiation (TMI) at a dose of 6Gy. Graft-versus-host disease prophylaxis will include cyclophosphamide 50 mg/kg on Day +3 and 4 along with tacrolimus and mycophenolate mofetil.

Official Title
-----------------
BMT-06: Phase II Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Cyclophosphamide and Post-Transplant Cyclophosphamide Conditioning for Partially HLA Mismatched (Haploidentical) Allogeneic Transplantation in Patients With Acute Leukemia and Myelodysplastic Syndrome (MDS)

Conditions
-----------------
Acute Leukemia, MDS

Intervention / Treatment
-----------------
* Device: Arm1
* Drug: Arm1
* Drug: Arm1
* Device: Arm 1
* Other: Arm1
* Drug: Arm1
* Drug: Arm1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient age 18-75 years Related donor who is, at minimum, Human Leukocyte Antigen (HLA) haploidentical. The donor and recipient must be identical at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype. In addition, unrelated donors who are mismatched at least one of the following loci: HLA-A, HLA-B, HLA-Cw, HLA-or DRB1. Eligible diagnoses are listed below. Patient must have one of the following: Relapsed or refractory acute leukemia (including AML or ALL in CR2 and primary refractory leukemia). Poor-risk AML in first remission: AML arising from MDS or a myeloproliferative disorder, or secondary AML Poor risk molecular features including but not limited to 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 Poor risk ALL in first remission: Poor risk cytogenetics: Philadelphia Chromosome, t(4;11), KMT2A translocation, t(8;14), complex karyotype (⩾ 5 chromosomal abnormalities) and low hypodiploidy (30-39 chromosomes)/near triploidy (60-78 chromosomes) Philadelphia-like ALL Presentation WBC >30 × 109 for B-ALL or >100 109 for T-ALL Age>35 Poor MRD clearance, defined as levels >1 × 10-3 after induction and levels >5 × 10-4 after early consolidation by flow cytometry Myelodysplastic syndromes (MDS) with at least one of the following poor-risk features: i. Poor-risk cytogenetics (including but not limited to 7/7q minus or complex cytogenetics) ii. IPSS score of INT-2 or greater iii. Treatment-related or Secondary MDS iv. MDS diagnosed before age 21 years v. Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy vi. Life-threatening cytopenias, including those generally requiring greater than weekly transfusions vii. Poor risk molecular features including but not limited to the presence of BCOR, ASXL1, p53 or RUNX1 mutations e. Mixed lineage and biphenotypic leukemia Adequate end-organ function as measured by: Left ventricular ejection fraction ≥ 40% 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 Exclusion Criteria: Presence of significant co morbidity as shown by: Left ventricular ejection fraction < 40% 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 Karnofsky score <70 History of cirrhosis Patients unable to sign informed consent Patient who have previously received radiation to >20% of bone marrow containing areas (assessed by radiation oncology physician)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: Single group assignment to Arm 1
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Device: Arm1|Experimental: Total marrow irradiation 1.5 Gray (Gy) twice a daily on days -3 and -2|
|Drug: Arm1|All patients will receive the following standard conditioning regimen: Fludarabine 30 mg/m2 IVPB daily from Day -6 (6 days before stem cell infusion) through Day -2|
|Drug: Arm1|IV cyclophosphamide 14.5 mg/kg intravenously prior to transplant on Days -6 and -5.|
|Device: Arm 1|Total body irradiation 2Gy on day -1.|
|Other: Arm1|Stem cell infusion on day 0.|
|Drug: Arm1|Tacrolimus IV initially in doses of 0.15 mg/kg/day for 3 days, followed by conversion to oral therapy (0.15 mg/kg twice daily)|
|Drug: Arm1|Cyclophosphamide on days 3 and 4 after transplant at a dose of 50mg/kg per day|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of 1 year Graft-Versus-Host Disease (GVHD) free | To evaluate the number of patients with acute leukemia or MDS that are GVHD free | 1 year | 
| Rate of 1 year Graft-Versus-Host Disease (GVHD) relapse free survival | To evaluate the number of patients with acute leukemia or MDS that are relapse free survival | 1 yeqar | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients with greater than or equal to grade 4 non-hematologic toxicities | Evaluate the incidence of greater than or equal to grade 4 non-hematologic toxicities | 1 year | 
| Engraftment rates | Engraftment rates at day 30 | 30 days | 
| Rates of incidence of full donor chimerism | Rates of incidence of full donor chimerism at day 30 | 30 days | 
| The rate of overall survival (OS) | The rate of overall survival (OS) | 1 year | 
| The rate of event free-survival (EFS) | The rate of event free-survival (EFS) | 1 year | 
| The rate of Grade II-IV and III-IV acute GVHD and limited/extensive chronic GVHD | The rate of Grade II-IV and III-IV acute GVHD and limited/extensive chronic GVHD | 1 year | 
| The rate of progression at 1 year post transplant | The rate of progression at 1 year post transplant | 1 year | 
| The rate of relapse at 1 year post transplant | The rate of relapse at 1 year post transplant | 1 year | 
| The rate of non-morality (NRM) at 1 year post transplant | The rate of non-morality (NRM) at 1 year post transplant | 1 year |