Total Marrow and Lymphoid Irradiation, Fludarabine, and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome
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|ClinicalTrials.gov Identifier: NCT03494569|
Recruitment Status : Recruiting
First Posted : April 11, 2018
Last Update Posted : November 20, 2018
|Condition or disease||Intervention/treatment||Phase|
|Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia in Remission Acute Myeloid Leukemia Acute Myeloid Leukemia in Remission Hematopoietic Cell Transplantation Recipient Minimal Residual Disease Myelodysplastic Syndrome Secondary Acute Myeloid Leukemia||Drug: Fludarabine Other: Laboratory Biomarker Analysis Drug: Melphalan Radiation: Total Marrow Irradiation||Phase 1|
I. To determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of total marrow and lymphoid irradiation (TMLI) with fixed doses of fludarabine and melphalan (FM100) as a preparative regimen in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) and who are not eligible for standard myeloablative regimens, with either a matched donor (Arm A) or a haploidentical donor (Arm B).
II. To describe toxicities attributable to TMLI by dose level in patients treated under this regimen.
I. To evaluate the safety of the regimen, at each dose level, by assessing the following: type, frequency, severity, attribution, time course and duration of adverse events, including acute/chronic graft versus host disease (GVHD), infection and delayed engraftment.
II. To investigate the temporal effect of bone marrow residual damage in alloHCT patients after TMLI/FM100.
III. To estimate overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.
IV. Assess minimal residual disease (MRD) from bone marrow aspirates on days 30, 100, and 180 post-transplant and describe its relation to TMLI dose level and patient disease status.
V. To evaluate effect of TMLI/FM100 conditioning on immune reconstitution after alloHCT in patients receiving stem cells from matched or haploidentical donors.
OUTLINE: This is a dose-escalation study of TMLI.
Participants undergo TMLI twice daily (BID) on days -8 to -5, and receive fludarabine intravenously (IV) on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
After completion of study treatment, participants are followed up twice weekly for 100 days, twice monthly for 6 months, and then monthly or yearly for up to 2 years.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of Escalating Doses of Total Marrow and Lymphoid Irradiation (TMLI) Combined With Fludarabine and Melphalan as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With High-Risk Acute Leukemia or Myelodysplastic Syndrome|
|Actual Study Start Date :||July 6, 2018|
|Estimated Primary Completion Date :||July 2020|
|Estimated Study Completion Date :||July 2020|
Experimental: Treatment (TMLI, fludarabine, melphalan)
Participants undergo TMLI BID on days -8 to -5, and receive fludarabine IV on days -4 to -2 and melphalan on day -2. Participants then undergo alloHCT on day 0.
Other Name: Fluradosa
Other: Laboratory Biomarker Analysis
Given as per City of Hope Standard Operating Procedure
Radiation: Total Marrow Irradiation
- Incidence of toxicity [ Time Frame: Up to 2 years ]Toxicity will be scored on both the Bearman scale and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5 scale. Toxicity information recorded in each patient will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity, and dose levels in each arm.
- Overall survival [ Time Frame: From start of protocol therapy up to 2 years ]Participants are considered a failure for this endpoint if they die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.
- Event-free survival [ Time Frame: From start of protocol therapy up to 2 years ]Participants are considered a failure for this endpoint if they relapse/progress or die, regardless of cause. Survival estimates will be calculated using the Kaplan-Meier method.
- Relapse/progression [ Time Frame: From start of protocol therapy up to 2 years ]Death without relapse/progression is considered a competing risk.
- Complete remission proportion [ Time Frame: At day 30 ]
- Non-relapse mortality [ Time Frame: Up to 2 years ]Participants are considered a failure for this endpoint if they die from causes other than disease relapse or progression.
- Incidence of infection [ Time Frame: Up to day 100 post-transplant ]Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. These data will be captured via case report form.
- Incidence of toxicities/adverse events (AEs) [ Time Frame: Up to 100 days post-transplant ]Toxicities that meet grade 3, 4, or 5 per the Bearman scale and CTCAE v 4.03 from day -9 to day -1, from day 0 to day +30, and again from day +31 to +100 post-transplant will be collected. Any AEs occurring from day -9 to day +30 will be followed until they resolve. Start and stop dates will also be recorded for any grade 4 neutropenia.
- Neutrophil recovery [ Time Frame: Up to 2 years ]This will be measured from stem cell infusion to the first to three consecutive days with neutrophil count greater than 0.5 x 10^9/l.
- Acute graft versus host disease of grades 2-4 and 3-4 [ Time Frame: Up to 100 days post-transplant ]Documented/biopsy proven acute graft versus host disease is graded according to National Institutes of Health (NIH) consensus staging. This measurement will be used to estimate the cumulative incidence.
- Chronic graft versus host disease [ Time Frame: Up to 2 years ]This will be scored according to NIH consensus staging and will be used to estimate the cumulative incidence.
- CD4+, CD8+ and CD56+16+ [ Time Frame: Up to 2 years ]Immunophenotyping of lymphocyte subsets will be determined by flow cytometry.
- Bone marrow (BM) residual damage [ Time Frame: Up to 2 years ]BM cellularity will be assessed using histology and clonogenic in vitro assays.
- Immune reconstitution [ Time Frame: Up to 2 years ]This will be monitored by flow cytometry analysis of peripheral blood mononuclear cells.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03494569
|United States, California|
|City of Hope Medical Center||Recruiting|
|Duarte, California, United States, 91010|
|Contact: Monzr M. Al Malki 626-301-4673 firstname.lastname@example.org|
|Principal Investigator: Monzr M. Al Malki|
|Principal Investigator:||Monzr Al Malki||City of Hope Medical Center|