This phase I/II trial studies the side effects and best dose of pralatrexate in combination with bendamustine and total-body irradiation (TBI) followed by a donor stem cell transplant in treating patients with T-cell non-Hodgkin lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Pralatrexate may block the growth of cancer cells and cause them to die. It is a type of dihydrofolate reductase (DHFR) inhibitor. Bendamustine may damage the DNA in cancer cells and cause them to die. It is a type of alkylating agent and a type of antimetabolite. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TBI is a type of radiation therapy that is given to the entire body. Giving pralatrexate with bendamustine and TBI before a donor stem cell transplant may help kill cancer cells in the body and help make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow.
OUTLINE: This is a phase I dose-escalation study of pralatrexate in combination with bendamustine and TBI followed by a phase II expansion study. Patients receive pralatrexate intravenously (IV) over 3-5 minutes on day -6, bendamustine IV over 60 minutes on days -5, -4, and -3, and TBI on day -1 or 0. Patients then undergo peripheral blood stem cell (PBSC) HCT on day 0. Patients also undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA) and lumbar puncture during screening, positron emission tomography-computed tomography (PET-CT), magnetic resonance imaging (MRI), bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated. After completion of study treatment, patients are followed up at 6 and 9 months and at 1, 1.5 and 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Given IV
Given IV
Undergo bone marrow biopsy/aspiration
Undergo bone marrow biopsy/aspiration
Undergo chest X-rays
Undergo PET-CT
Undergo ECHO
Undergo lumbar puncture
Undergo MRI
Undergo MUGA
Undergo PBSC HCT
Undergo PET-CT
Ancillary studies
Undergo TBI
Undergo blood sample collection
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Incidence and severity of treatment-emergent adverse events and treatment-emergent serious adverse events (Phase 1)
In addition, clinically significant laboratory abnormalities, changes in vital signs, and changes in physical examination following allogeneic hematopoietic cell transplantation (allo-HCT). Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Will be summarized by grades and put in different tables by dose.
Time frame: From pralatrexate dosing on day -6 to 28 days post-transplant
Proportion of enrolled patients with T-cell non-Hodgkin lymphoma who successfully proceed to allogeneic-hematopoietic cell transplant (HCT) (Phase 2)
Will compare it with the historical rate of 31%.
Time frame: Up to 2 years post-transplant
Non-relapse mortality (NRM) (Phase 1)
Time frame: Up to day 100 post-transplant
Incidence and severity of grade II-IV acute graft-versus-host disease (GVHD) (Phase 2)
Group comparisons will be performed using Gray's test, and multivariable analyses will be conducted using cause-specific Cox model to assess the effect of covariates. The cumulative incidence of acute will be estimated using the cumulative incidence function.
Time frame: Up to day 100 post-transplant
Incidence and severity of grade III-IV acute GVHD (Phase 2)
Group comparisons will be performed using Gray's test, and multivariable analyses will be conducted using cause-specific Cox model to assess the effect of covariates. The cumulative incidence of acute will be estimated using the cumulative incidence function.
Time frame: Up to day 100 post-transplant
Incidence and severity of chronic GVHD requiring systemic immunosuppressive therapy (Phase 2)
Group comparisons will be performed using Gray's test, and multivariable analyses will be conducted using cause-specific Cox model to assess the effect of covariates. Group comparisons will be performed using Gray's test, and multivariable analyses will be conducted using cause-specific Cox model to assess the effect of covariates. The cumulative incidence will be estimated using the cumulative incidence function.
Time frame: At 1 year post-transplant
Disease response rate (Phase 2)
Proportion and counts will be calculated with an exact 95% confidence intervals.
Time frame: At day 100 post-transplant
Duration of remission from response until documented relapse or progression (Phase 2)
Time frame: From response until documented relapse or progression, per disease-specific response criteria up to 2 years post-transplant
Rates of donor chimerism ≥ 90% in peripheral blood CD3+ and CD33+ cell lines
Proportion and counts will be calculated with an exact 95% confidence intervals. Donor chimerism will be summarized by the observed levels and levels categorized as ≥ 95%, 50% - 94%, 5% - 49%, or \< 5%.
Time frame: Up to day 80 post-transplant
Disease-free survival (Phase 2)
Will be defined as the proportion of patients who are alive and free of disease. The Kaplan-Meier method will be used to estimate the median with 95% confidence intervals. Log-rank test will be used for group comparison. Proportion and counts will be calculated with an exact 95% confidence intervals.
Time frame: From day 0 (date of graft infusion) to the first of: Relapse/progression of the underlying disease, or death from any cause, assessed up to 1 year post-transplant
NRM (Phase 2)
Time frame: Up to day 100 post-transplant
Overall survival (Phase 2)
The Kaplan-Meier method will be used to estimate the median with 95% confidence intervals. Log-rank test will be used for group comparison.
Time frame: Up to 2 years post-transplant
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