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

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)

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

Study Overview

• Status: Recruiting
• Conditions: Acute Leukemia; MDS
• Intervention / Treatment: Device: Arm1; Drug: Arm1; Drug: Arm1; Device: Arm 1; Other: Arm1; Drug: Arm1; Drug: Arm1

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.

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rondelli Damiano, MD; Phone Number: 312-996-6179; Email: drond@uic.edu
• Study Contact Backup: Name: Marisol Vega, MS; Phone Number: 312-335-5035; Email: vegam35@uic.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • University of Illinois Cancer Center
      • Contact: Rondelli Damiano, MD; Phone Number: 312-996-6179; Email: drond@uic.edu
      • Contact: Marisol Vega, MS; Phone Number: 312-355-5035; Email: vegam35@uic.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

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

Collaborators and Investigators

• Sponsor: University of Illinois at Chicago
• Investigators: Principal Investigator: Rondelli Damiano, MD, University of Illinois at Chicago

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2020
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: November 11, 2019
• First Submitted That Met QC Criteria: December 3, 2019
• First Posted (Actual): December 5, 2019

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Calcineurin Inhibitors; Complement Inactivating Agents; Cyclophosphamide; Fludarabine; Tacrolimus; Complement Factor H
• Other Study ID Numbers: 2019-1149

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes