This is a phase I/II clinical trial on the use of total marrow irradiation (TMI) given concurrently with fludarabine, a chemotherapy drug commonly used to treat leukemia, as a myeloablative therapy for patients undergoing Allo-HSCT. TMI is a targeted technique to deliver radiation to the bone marrow while minimizing dose to other normal organs in the body. In phase I of the clinical study, the dose of radiation to the bone marrow will be incrementally increased to determine the highest tolerated TMI dose. In phase II, the effectiveness of the TMI-fludarabine conditioning regimen utilizing that dose of radiation will be studied. Acute and long-term toxicity data as well as quality of life data will also be studied. \*Stopping criteria was met during the first dose level cohort in Phase l. The trial will not continue into Phase II as originally planned.
This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of intensity modulated radiation therapy based total marrow irradiation (TMI) concurrent with fludarabine as 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 and relapsed or refractory 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) Primary Objectives: Phase I: Determine the MTD of TMI given concurrently with fludarabine (fixed at 150 mg/m2) 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. 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 * Stopping criteria was met during the first dose level cohort in Phase l. The trial will not continue into Phase II as originally planned.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Fludarabine 30 mg/m2/day IV (total 5 doses) administered days -7 through -3 of conditioning regimen
TMI will be delivered twice a day, at least 6 hours apart, on days -7 through -3 (total of 10 fractions) of conditioning regimen
Indiana University Melvin & Bren Simon Cancer Center
Indianapolis, Indiana, United States
Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine- Phase I only
Time frame: Day -7 of conditioning regimen through 30 days post transplant (37 days)
Maximum-tolerated dose (MTD) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine-Phase I only
Time frame: Day -7 of conditioning regimen through 30 days post transplant (37 days)
Overall survival (OS) rate 1 year post transplant-Phase II only
Time frame: 1 year
Frequency of non hematologic toxicities
Time frame: 100 days
Incidence of infection
Time frame: 100 days
Type of infections
Time frame: 100 days
Incidence of graft versus host disease (GvHD)
Time frame: 100 days
Incidence of chronic graft versus host disease (GvHD)
Time frame: 2 years
Incidence of sinusoidal obstruction syndrome (SOS)
Time frame: 100 days
Incidence of pneumonitis
Time frame: 100 days
Incidence of mucositis
Time frame: 100 days
Time to engraftment of neutrophils
Time frame: from 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: from date of transplant until he first of seven consecutive days after transplantation during which the platelet count is greater than or equal to 20 x10^9/liters without transfusion.
Disease response rate
Time frame: Day 30 after transplant (30 days)
Incidence of relapse mortality
Time frame: 30 days
Incidence of relapse mortality
Time frame: 100 days
Incidence of relapse mortality
Time frame: 1 year
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
Disease-Free Survival
Time frame: 2 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: Screening (at simulation), day +180, day +365, + 2 years from transplant (approximately 2 years)
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