IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT
Sponsor:
Naoyuki G. Saito, M.D., Ph.D.
Collaborators:
Information provided by (Responsible Party):
Naoyuki G. Saito, M.D., Ph.D.，Indiana University School of Medicine
| Tracking Information | |||
|---|---|---|---|
| First Submitted Date ICMJE | October 2, 2018 | ||
| First Posted Date ICMJE | October 4, 2018 | ||
| Last Update Posted Date | October 4, 2018 | ||
| Actual Study Start Date ICMJE | August 29, 2018 | ||
| Estimated Primary Completion Date | March 31, 2023 (Final data collection date for primary outcome measure) | ||
| Current Primary Outcome Measures ICMJE |
Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine[ 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[ Time Frame: Day -7 of conditioning regimen through 30 days post transplant (37 days) ] Overall survival (OS) rate 1 year post transplant[ Time Frame: 1 year ] |
||
| Original Primary Outcome Measures ICMJE | Same as current | ||
| Current Secondary Outcome Measures ICMJE |
|
||
| Descriptive Information | |||
| Brief Title ICMJE | IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT |
||
| Official Title ICMJE | 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 |
||
| Brief Summary | The purpose of this study is to find the maximum tolerated dose (MTD) of Total Marrow Irradiation (TMI), a type of radiation treatment administered with fludarabine, a type of chemotherapy to prepare patients for allogeneic hematopoietic stem cell transplantation (Allo-HSCT). The study will also examine the efficacy of fludarabine and total marrow radiation treatment. Patients in this study will receive fludarabine and TMI during their conditioning regimen for 7 days prior to Allo-HSCT |
||
| 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) in combination with 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 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 component: 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 component: 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. | ||
| Study Type ICMJE | Interventional | ||
| Study Phase | Phase 1/Phase 2 | ||
| Study Design ICMJE | Allocation: Intervention Model: Sequential Assignment Intervention Model Description: Standard "3+3" phase I design of dose escalation using 3 patients per dose level cohort with an expansion to 6 patients at the MTD will be used during the phase 1 component. We will treat 3 patients at the initial dose level of TMI. If no dose-limiting toxicity [DLT] is observed, the next cohort of three patients is treated at the next higher dose level. If 1 of the 3 patients demonstrates DLT, an additional 3 patients are treated at that dose level. If only 1 of the 6 shows DLT, the next cohort of three patients is entered at the next dose level. If 2 or more of the 6 demonstrate DLT, the MTD is defined as the previous dose level. If no DLT is observed in the final dose level, the number of patients treated will be expanded to 6. The phase II component will enroll additional patients at the defined MTD level. Masking: Interventional Masking Description: Primary Purpose: Treatment |
||
| Condition ICMJE | |||
| Intervention ICMJE |
|
||
| Study Arms |
|
||
| Recruitment Information | |||
| Recruitment Status ICMJE | Recruiting | ||
| Estimated Enrollment ICMJE |
53 | ||
| Original Estimated Enrollment ICMJE | Same as current | ||
| Estimated Study Completion Date | March 31, 2024 | ||
| Estimated Primary Completion Date | March 31, 2023 (Final data collection date for primary outcome measure) | ||
| Eligibility Criteria ICMJE | 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: - Blasts 10-19% 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 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. Active infection: Patients with active infections requiring oral or intravenous antimicrobial drugs are not eligible for enrollment until resolution of infection. 3. HIV seropositive patients. 4. Pregnant or nursing females are excluded from this study. 5. Prior radiation therapy 6. Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation | ||
| Sex/Gender |
|
||
| Ages | 18 Years and older (Adult, Older Adult) | ||
| Accepts Healthy Volunteers | No | ||
| Listed Location Countries ICMJE | United States | ||
| Removed Location Countries | |||
| Administrative Information | Has Data Monitoring Committee | Yes | |
| U.S. FDA-regulated Product |
Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No |
||
| IPD Sharing Statement |
|
||
| Responsible Party | Naoyuki G. Saito, M.D., Ph.D.，Indiana University School of Medicine | ||
| Study Sponsor ICMJE | Naoyuki G. Saito, M.D., Ph.D. | ||
| Collaborators ICMJE | |||
| Investigators ICMJE |
|
||
| PRS Account | Indiana University School of Medicine | ||
| Verification Date | October 2018 | ||
|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
|||
请使用微信扫码报名
京公网安备 11010102003638号