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 Allogeneic Transplantation in Patients With Acute Leukemia and Myelodysplastic Syndrome (MDS)

Overview

This study is being done to see if the addition of a targeted form of radiation to standard conditioning regimen will increase the amount of cancer cells that are killed off in the bone marrow and reduce the chances that your disease may return. This description is called Intensity Modulated Total Marrow Irradiation (IM-TMI).

Detailed description

This is a single arm phase II clinical trial. The usual conditioning regimen for haploidentical transplant is the use of chemotherapy (fludarabine/cyclophosphamide) before the transplant and further chemotherapy with cyclophosphamide after the transplant. In addition, a small dose of radiation is also given.

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). Graft-versus-host disease prophylaxis will include cyclophosphamide 50 mg/kg on Day +3 and 4 along with tacrolimus and mycophenolate mofetil.

Interventions

• Radiation Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Experimental: Total marrow irradiation 1.5 Gray (Gy) twice a daily on days -3 and -2
• Drug Conditioning regimen with half-matched (haploidentical) stem cell transplant
  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 Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Cyclophosphamide 14.5 mg/kg intravenously prior to transplant on Days -6 and -5
• Device Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Total body irradiation 2Gy on Day -1.
• Other Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Stem cell infusion on Day 0.
• Drug Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Mesna 14.5 mg/kg IV starting 30 minutes prior to cyclophosphamide on Days -6 and -5 and continuing for at least 12 hours after end of cyclophosphamide
• Drug Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Cyclophosphamide 50 mg/kg IV on Days 3 and 4 after transplant at a dose of 50mg/kg per day
• Drug Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Mesna 10 mg/kg IV every 4 hours for 10 doses starting 1 hour prior to cyclophosphamide on Days 3 and 4
• Drug Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Tacrolimus 0.03 mg/kg IBW Q24H starting on Day 5
• Drug Conditioning regimen with half-matched (haploidentical) stem cell transplant
  Mycophenolate mofetil (MMF) 15 mg/kg PO TID (maximum daily dose of 3g/day) starting on Day 5

Primary outcome measures

• Rate of 1 year Graft-Versus-Host Disease (GVHD) free, relapse free survival (GRFS) survival [Time frame: 1 year]

Secondary outcome measures (9)

• The number of patients with greater than or equal to grade 4 non-hematologic toxicities [Time frame: 1 year post-stem cell transplant]
• Engraftment rates [Time frame: 30 days post-stem cell transplant]
• Rates of incidence of full donor chimerism [Time frame: 30 days post-stem cell transplant]
• The rate of overall survival (OS) [Time frame: 1 year post-stem cell transplant]
• The rate of event free-survival (EFS) [Time frame: 1 year post-stem cell transplant]
• The rate of Grade II-IV and III-IV acute GVHD and limited/extensive chronic GVHD [Time frame: 1 year post-stem cell transplant]
• The rate of progression at 1 year post transplant [Time frame: 1 year post-stem cell transplant]
• The rate of relapse at 1 year post transplant [Time frame: 1 year post-stem cell transplant]
• The rate of non-morality (NRM) at 1 year post transplant [Time frame: 1 year post-stem cell transplant]

Eligibility criteria

Inclusion criteria

• Patient age 18-75 years
• Related donor who is, at minimum, Human Leukocyte Antigen (HLA) haploidentical or mismatched unrelated donor.

• Haploidentical: The donor and recipient must be identical in 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 4/8 if using HLA-A,-B,-DRB1,-Cw, or 5/10 if using HLA-A,-B,-Cw ,-DRB1, and -DQB1, will be considered evidence that the donor and recipient share one HLA haplotype.
• Unrelated donors: unrelated donors who are mismatched in one or more of the following loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1,HLA-DQB1- can be included with a maximum of 4/8 or 5/10 mismatches.
• 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
• Mixed lineage and biphenotypic leukemia
• Adequate end-organ function as measured by:

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

Exclusion criteria

• Presence of significant co morbidity as shown by:

• a. Left ventricular ejection fraction < 40%
• b. Bilirubin > 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST > 5 x ULN
• c. FEV1 and FVC < 50% of predicted or DLCO <50% of predicted once corrected for anemia
• d. Karnofsky score <70
• e. 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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Illinois Cancer Center — Chicago

Identifiers

NCT: NCT04187105 · 2019-1149

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗