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

Acute Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04187105
• Other study ID #: 2019-1149
• Status: Recruiting
• Phase: Phase 2
• Start date: January 27, 2020
• Est. completion date: November 2024

Study information

• Verified date: September 2023
• Source: University of Illinois at Chicago
• Contact: Rondelli Damiano, MD
• Phone: 312-996-6179
• Email: drond[@]uic.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 27
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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)

Related Conditions & MeSH terms

• Acute Leukemia
• Leukemia
• MDS

Intervention

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
• 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)
• Arm1
Cyclophosphamide on days 3 and 4 after transplant at a dose of 50mg/kg per day

Locations

Country	Name	City	State
United States	University of Illinois Cancer Center	Chicago	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
University of Illinois at Chicago

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Engraftment rates	Engraftment rates at day 30	30 days
Secondary	Rates of incidence of full donor chimerism	Rates of incidence of full donor chimerism at day 30	30 days
Secondary	The rate of overall survival (OS)	The rate of overall survival (OS)	1 year
Secondary	The rate of event free-survival (EFS)	The rate of event free-survival (EFS)	1 year
Secondary	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
Secondary	The rate of progression at 1 year post transplant	The rate of progression at 1 year post transplant	1 year
Secondary	The rate of relapse at 1 year post transplant	The rate of relapse at 1 year post transplant	1 year
Secondary	The rate of non-morality (NRM) at 1 year post transplant	The rate of non-morality (NRM) at 1 year post transplant	1 year