NCT05201183

A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) Followed by Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies

• Status: Withdrawn
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: Naoyuki G. Saito, M.D., Ph.D. · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of total marrow irradiation (TMI) followed by fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk leukemia and myelodysplasia.

Detailed description

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of total marrow irradiation (TMI) followed by fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk leukemia and myelodysplasia. TMI, which allows for conformal dosing of target bone marrow tissue while giving lower doses to organs at risk, is considered by many to be a superior alternative to conventional total body irradiation (TBI). Through the use of TMI, it is possible to escalate the dose of radiation to the bone marrow while keeping the dose to normal organs at acceptable levels, effectively widening the therapeutic window of this modality. This conditioning regimen will be tried in patients with relapsed or refractory hematologic malignancies. Primary Objectives: Phase I: Determine the MTD of TMI (delivered twice a day for 5 days) followed by fludarabine (fixed at 150 mg/m2 given over 5 days) as a conditioning regimen for Allo-HSCT for patients with high risk (relapsed/refractory) acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelogenous leukemia (CML). Phase II: Single-arm exploratory study to expand the cohort at the MTD level to estimate 1- year overall survival (OS), with the objective of increasing the OS from the historical rate of 30% (null hypothesis) to 50% (alternate hypothesis) with 80% power and a one-sided type I error of 0.05. Secondary Objectives 1. Describe the extramedullary toxicity and the incidence of complications, including mucositis, acute and chronic graft versus host disease (GvHD), sinusoidal obstruction syndrome (SOS), and pneumonitis. 2. Describe the time to engraftment of neutrophils and platelets 3. Describe the disease response rate at Day 30 after transplantation 4. Describe the overall survival and disease-free survival 5. Describe the cumulative incidence of relapse and non-relapse mortality 6 6. Determine the correlation between plasma/serum markers and radiation induced acute and long term toxicities. 7. Describe the quality of life metrics of participating subjects

Conditions

• Acute Myeloid Leukemia
• Chronic Myeloid Leukemia
• Acute Lymphocytic Leukemia
• Myelodysplastic Syndromes

Interventions

Type	Name	Description
COMBINATION_PRODUCT	Fludarabine + Total Marrow Irradiation	Patients will receive total marrow irradiation TMI on Day -11 to Day -7 in two fractions per day. The TMI dose will be escalated in successive cohorts compromised of 3-6 patients as follows: Cohort 1 1.4 (Gy/fraction) Cohort 2: 1.6 (Gy/fraction) Cohort 3 1.8 (Gy/fraction) Cohort 4 2.0 (Gy/fraction) Cohort 5 2.2 (Gy/fraction) Patients will receive Fludarabine (30 mg/m2/day) on Day -6 to Day -2 followed by allo-HSCT on Day 0.

Timeline

• Start date: 2023-10-01
• Primary completion: 2027-04-01
• Completion: 2029-04-01
• First posted: 2022-01-21
• Last updated: 2023-12-11

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study
• FDA-regulated device study