Description:
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.
Title
- Brief Title: IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT
- Official Title: A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) With Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies
Clinical Trial IDs
- ORG STUDY ID:
IUSCC-0652
- NCT ID:
NCT03696537
Conditions
- Acute Myeloid Leukemia
- Chronic Myeloid Leukemia
- Acute Lymphocytic Leukemia
- Myelodysplastic Syndromes
Interventions
Drug | Synonyms | Arms |
---|
Fludarabine | | Fludarabine + Total Marrow Irradiation |
Purpose
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.
Detailed Description
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Fludarabine + Total Marrow Irradiation | Experimental | | |
Eligibility Criteria
Inclusion Criteria:
1. Patients must be diagnosed with one of the following conditions:
Acute Myeloid Leukemia (AML) who are not in complete remission, and who have either
primary refractory or relapsed disease, and who do not have more than one of the
following adverse factors:
1. Duration of first CR < 6 months (if previously in CR)
2. Poor risk karyotype including any of the following: complex karyotype with ≥3
clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q
abnormalities, t(6;9), t(9;22), 17p abnormalities [or TP53 mutations] or
monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used
for eligibility criteria determination.
3. Circulating peripheral blood blasts at time of enrollment
4. Karnofsky performance status <90%
Acute Lymphocytic Leukemia (ALL) who are not in complete remission, and who have
either primary refractory or relapsed disease, and who do not have more than one of
the following adverse factors:
1. First refractory relapse. Patients in second or subsequent relapse are excluded.
2. Donor is CMV seropositive
3. Bone marrow blasts >25% (within 30 days of admission)
4. Age >40 years
Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than
4.5 (i.e., high- or very-high risk).
Chronic Myelogenous Leukemia (CML) in either
1. Accelerated phase, defined by any of the following:
- 10-19% blasts in peripheral blood white cells or bone marrow
- Peripheral blood basophils at least 20%
- Persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or
persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy
- Increasing spleen size and increasing white blood cell (WBC) count
unresponsive to therapy
- Cytogenetic evidence of clonal evolution (i.e., the appearance of an
additional genetic abnormality that was not present in the initial specimen
at the time of diagnosis of chronic phase)
2. Chronic phase provided a complete hematologic remission was not achieved by 3
months or a complete cytogenetic remission by 18 months and the patient had
received at least 2 tyrosine kinase inhibitors.
2. Patient age 18-65 years old at time of consent
3. Availability of a consenting human leukocyte antigens(HLA) -matched donor
4. Karnofsky Performance Status 70% or higher
5. Required baseline laboratory values:
1. Estimated creatinine clearance ≥ 60 ml/min
2. Aspartate aminotransferase and alanine aminotransferease ≤ 2.5 x upper limit of
normal value
3. Bilirubin ≤ 1.5 x upper limit of normal value
6. Required baseline cardiac function of left ventricular ejection fraction (LVEF) > 45
- corrected
7. Required baseline pulmonary function of lung diffusing capacity (DLCO) > 45 %
predicted (corrected for hemoglobin)
8. Patient must be capable of understanding the investigational nature of this study,
potential risks and benefits of the study, and be able to provide a valid informed
consent.
Exclusion Criteria:
1. Patients with ALL who are in second or subsequent relapse
2. HIV seropositive patients.
3. Pregnant or nursing females are excluded from this study.
4. Prior radiation therapy
5. Patients who have had a prior autologous or allogeneic bone marrow or stem cell
transplantation
Maximum Eligible Age: | 65 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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) |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Frequency of non hematologic toxicities |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of infection |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Type of infections |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of graft versus host disease (GvHD) |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of chronic graft versus host disease (GvHD) |
Time Frame: | 3 years |
Safety Issue: | |
Description: | |
Measure: | Incidence of sinusoidal obstruction syndrome (SOS) |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of pneumonitis |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of mucositis |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | 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 |
Safety Issue: | |
Description: | |
Measure: | 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. |
Safety Issue: | |
Description: | |
Measure: | Disease response rate |
Time Frame: | Day 30 after transplant (30 days) |
Safety Issue: | |
Description: | |
Measure: | Incidence of relapse mortality |
Time Frame: | 30 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of relapse mortality |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of relapse mortality |
Time Frame: | 1 year |
Safety Issue: | |
Description: | |
Measure: | Incidence of non-relapse mortality |
Time Frame: | 30 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of non-relapse mortality |
Time Frame: | 100 days |
Safety Issue: | |
Description: | |
Measure: | Incidence of non-relapse mortality |
Time Frame: | 1 year |
Safety Issue: | |
Description: | |
Measure: | Disease-Free Survival |
Time Frame: | 3 years |
Safety Issue: | |
Description: | |
Measure: | Mean Quality of Life (QOL) as measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4 |
Time Frame: | Screening (at simulation), day +180, day +365, + 2 years from transplant (approximately 2 years) |
Safety Issue: | |
Description: | 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 |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Naoyuki G. Saito, M.D., Ph.D. |
Trial Keywords
- Radiation
- Total Marrow Irradiation
- Fludarabine
- Bone Marrow Transplantation
Last Updated
March 19, 2021