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.
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
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
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.
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Indianapolis, Indiana, United States
Maximum tolerated dose of Total Marrow Irradiation (TMI) followed by 150 mg/m2 fludarabine- Phase I only
Time frame: Day -10 of conditioning regimen through 30 days post transplant (40 days)
Overall survival (OS) rate 1 year post transplant-Phase II only
Time frame: 1 year
Frequency of non hematologic toxicity
Time frame: 100 days
Incidence of mucositis
Time frame: 100 days
Incidence of acute graft versus host disease
Time frame: 100 days
Incidence of chronic graft versus host disease
Time frame: 100 days
Incidence of sinusoidal obstruction syndrome
Time frame: 100 days
Incidence of pneumonitis
Time frame: 100 days
Time to engraftment of neutrophils
Time frame: rom date of transplant to the first of three consecutive days after transplantation during which the absolute neutrophil count (ANC) is greater than or equal to 0.5 x 10^9/liter
Time to engraftment of platelets
Time frame: the time from Day 0 to the first of seven consecutive days after transplantation during which the platelet count is at least 20 x109/l without transfusion support.
Disease free survival
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Time frame: 3 years
Mean Quality of Life (QOL) as measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4
50 item likert type scale with responses measuring from 0-4 (where 0 = not at all; 1 = a little bit; 2 = somewhat, 3 = quite; and 4 = very much) with higher scores correlating to higher QOL
Time frame: At screening, Day +30, Day +180, Day +365, Day +730 and Day +1095 from transplant (approximately 3 years)
Incidence of non-relapse mortality
Time frame: 30 days
Incidence of non-relapse mortality
Time frame: 100 days
Incidence of non-relapse mortality
Time frame: 1 year
Incidence of relapse mortality
Time frame: 1 year
Incidence of relapse mortality
Time frame: 30 days
Incidence of relapse mortality
Time frame: 100 days
Overall Survival
Time frame: Day +30, Day +100 and 1 year (approximately 3 years)