Clinical trial NCT04187105: BMT-06: Study of Intensity Modulated Total Marrow Irradiation (IM-TMI)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Leukemia
MDS
Lead sponsor: University of Illinois at Chicago
Sponsor class: OTHER
First posted: 2019-12-05
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single group assignment to Arm 1
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Patient age 18-75 years
2. 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.
3. Eligible diagnoses are listed below. Patient must have one of the following:

   1. Relapsed or refractory acute leukemia (including AML or ALL in CR2 and primary refractory leukemia).
   2. 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
   3. 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
   4. 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
4. Adequate end-organ function as measured by:

   1. Left ventricular ejection fraction ≥ 40%
   2. Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \< 5 x ULN
   3. FEV1 and FVC \> 50% of predicted

Exclusion Criteria:

1. Presence of significant co morbidity as shown by:

   1. Left ventricular ejection fraction \< 40%
   2. Bilirubin \> 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \> 5 x ULN
   3. FEV1 and FVC \< 50% of predicted or DLCO \<50% of predicted once corrected for anemia
   4. Karnofsky score \<70
   5. History of cirrhosis
2. Patients unable to sign informed consent
3. Patient who have previously received radiation to \>20% of bone marrow containing areas (assessed by radiation oncology physician)

Primary outcomes:
measure: Rate of 1 year Graft-Versus-Host Disease (GVHD) free
timeFrame: 1 year
measure: Rate of 1 year Graft-Versus-Host Disease (GVHD) relapse free survival
timeFrame: 1 yeqar
Secondary outcomes:
measure: The number of patients with greater than or equal to grade 4 non-hematologic toxicities
timeFrame: 1 year
measure: Engraftment rates
timeFrame: 30 days
measure: Rates of incidence of full donor chimerism
timeFrame: 30 days
measure: The rate of overall survival (OS)
timeFrame: 1 year
measure: The rate of event free-survival (EFS)
timeFrame: 1 year
measure: The rate of Grade II-IV and III-IV acute GVHD and limited/extensive chronic GVHD
timeFrame: 1 year
measure: The rate of progression at 1 year post transplant
timeFrame: 1 year
measure: The rate of relapse at 1 year post transplant
timeFrame: 1 year
measure: The rate of non-morality (NRM) at 1 year post transplant
timeFrame: 1 year
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Illinois Cancer Center
state: Illinois
Study officials:
affiliation: University of Illinois at Chicago
name: Rondelli Damiano, MD
role: PRINCIPAL_INVESTIGATOR
References: