Pralatrexate and Bendamustine With 3 Gy TBI as a New Reduced Intensity Conditioning (RIC) Regimen for Allogeneic HCT for T-Cell Lymphoma Patients Who Are in Untreated R/R, or in Remission With MRD
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Incidence and severity of treatment-emergent adverse events and treatment-emergent serious adverse events (Phase 1)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years with an HCT-Comorbidity Index (CI) ≤ 5 for patients over 60 years
- •T-cell non-Hodgkin lymphoma (T-NHL) (2022 World Health Organization [WHO] criteria) including primary cutaneous T-NHL that is in untreated or unsuccessfully treated first or subsequent relapse. Patients in morphologic remission (i.e. < 5% blasts in the bone marrow, if involved) but evidence of minimal residual disease (MRD) by positron emission tomography-computed tomography (PET-CT), multiparameter flow cytometry, cytogenetics/fluorescence in situ hybridization (FISH), or molecular means will be eligible for trial participation
- •The use of bridging chemotherapy prior to initiation of study treatment is allowed. Patients with symptoms/signs of hyperleukocytosis, white blood cells (WBC) > 100,000/µL, or with concern for other complications of high tumor burden of high tumor dynamics (e.g. disseminated intravascular coagulation) can be treated with leukapheresis or may receive a cycle of salvage chemotherapy prior to start of study treatment
- •Karnofsky score ≥ 70; Eastern Cooperative Oncology Group (ECOG) 0-1
- •Adequate cardiac function defined as absence of decompensated congestive heart failure and/or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 45%
- •Bilirubin ≤ 2.5 x institutional upper limit of normal unless elevation is thought to be due to hepatic infiltration by lymphoma, Gilbert's syndrome, or hemolysis
- •Adequate pulmonary function defined as absence of oxygen (O2) requirements and either diffusion capacity of the lung for carbon monoxide (DLCO) corrected ≥ 70%mmHg or DLCO corrected 60-69%mmHg and partial pressure of oxygen (pO2) ≥ 70mmHg
- •Creatinine clearance ≥ 60 mL/min
- •Prior autologous HCT is permissible if relapse occurred > 6 months after HCT
- •An human leukocyte antigen (HLA)-matched sibling/unrelated donor, mismatched unrelated donor or haploidentical donor for collection of stimulated peripheral blood stem cells must be identified and readily available
- •If the patient has received pralatrexate or bendamustine before and has been sensitive to this regimen, defined as MRD negative complete response (CR) immediately after receiving the treatment and which lasts ≥ 1 year, eligibility will be determined on a case-by-case basis by the study principal investigator (PI)
- •Ability to understand and sign a written informed consent document (or legal representative)
- •RELATED DONOR: Related to the patient and genotypically or phenotypically identical for HLA-A, B, C, DRB1 and DQB
- •Phenotypic identity must be confirmed by high-resolution typing
- •MATCHED UNRELATED DONOR: Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR
- •MATCHED UNRELATED DONOR: Mismatched for a single allele without antigen mismatching at HLA-A, B, or C as defined by high resolution typing but otherwise matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing
- •MATCHED UNRELATED DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. The recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT. If the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained. The donor should be excluded if any of the cytotoxic cross match assays are positive. For those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results. A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion.
- •MATCHED UNRELATED DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed.
- •MISMATCHED UNRELATED DONOR: HLA-matching must be based on results of high resolution typing at HLA-A, -B, -C, -DRB1, and -DQ
- •MISMATCHED UNRELATED DONOR: Mismatch for one HLA class I antigen with or without an additional mismatch for one HLA-class I allele but matched for HLA-DRB1 and HLA-DQ
- •MISMATCHED UNRELATED DONOR: Mismatched for two HLA class I alleles but matched for HLA-DRB1 and HLA-DQ
- •MISMATCHED UNRELATED DONOR: HLA class I HLA-A, -B, -C allele matched donors allowing for any one or two DRB1 and/or DQB1 antigen/allele mismatch
- •MISMATCHED UNRELATED DONOR: If the patient is homozygous at the mismatch HLA class I locus or II locus, the donor must be heterozygous at that locus and one allele must match the patient (i.e., patient is homozygous A*01:01 and donor is heterozygous A*01:01, A*02:01). This mismatch will be considered a one-antigen mismatch for rejection only
- •HAPLOIDENTICAL DONOR: Donors must be haploidentical relatives of the patients. Donor-recipient compatibility will be tested through HLA typing at high resolution for the HLA loci (-A, -B, -C, -DRB1, -DQB1). Donor and recipient should share at least 5/10 HLA loci
- •HAPLOIDENTICAL DONOR: Age ≥ 18 years
- •HAPLOIDENTICAL DONOR: Weight ≥ 40 kg
- •HAPLOIDENTICAL DONOR: Donor must meet the selection criteria as defined by the Foundation of the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB) guidelines
- •HAPLOIDENTICAL DONOR: In case of more available haploidentical donors, selection criteria should include, in this order:
- •For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor
- •Red blood cell compatibility
- •Red blood cell (RBC) cross match compatible
- •Minor ABO incompatibility
- •Major ABO incompatibility
排除标准
- •Active central nervous system (CNS) disease
- •Concomitant illness associated with a likely survival of < 1 year
- •Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with antimicrobials and/or controlled or stable. Patients with fever thought to be likely secondary to lymphoid malignancy are eligible
- •Known hypersensitivity or contraindication to any study drug used in this trial
- •Pregnancy or lactation
- •Concurrent treatment with any other approved or investigational anti-lymphoma agent at the time of starting conditioning
- •HAPLOIDENTICAL DONOR: Since detection of anti-donor-specific antibodies (anti-DSA) is associated with higher graft rejection rate, patients will be screened for anti-DSA pre-transplant. Patient with DSA mean fluorescent intensity (MFI) < 5000 after desensitization treatment, will be considered eligible to participate in the study
研究组 & 干预措施
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Chest Radiography (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Bendamustine (Drug)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Pralatrexate (Drug)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Echocardiography Test (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Positron Emission Tomography (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Lumbar Puncture (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Computed Tomography (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Multigated Acquisition Scan (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Peripheral Blood Stem Cell Transplantation (Procedure)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Questionnaire Administration (Other)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Total-Body Irradiation (Radiation)
Treatment (pralatrexate, bendamustine, TBI, PBSC HCT)
Patients receive pralatrexate 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 PBSC HCT on day 0. Patients also undergo ECHO or MUGA and lumbar puncture during screening, PET-CT, MRI, bone marrow biopsy/aspiration, and blood sample collection throughout the study. In addition, patients may undergo chest X-rays as clinically indicated.
干预措施: Biospecimen Collection (Procedure)
结局指标
主要结局
Incidence and severity of treatment-emergent adverse events and treatment-emergent serious adverse events (Phase 1)
时间窗: From pralatrexate dosing on day -6 to 28 days post-transplant
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.
Proportion of enrolled patients with T-cell non-Hodgkin lymphoma who successfully proceed to allogeneic-hematopoietic cell transplant (HCT) (Phase 2)
时间窗: Up to 2 years post-transplant
Will compare it with the historical rate of 31%.
Incidence and severity of treatment emergent adverse events and treatment emergent serious adverse events
时间窗: From pralatrexate dosing on day -6 to 100 days post-transplant
In addition, clinically significant laboratory abnormalities, changes in vital signs, and changes in physical examination following allogeneic hematopoietic cell transplantation (allo-HCT).
次要结局
- NRM (Phase 2)(Up to day 100 post-transplant)
- Non-relapse mortality (NRM) (Phase 1)(Up to day 100 post-transplant)
- Incidence and severity of grade II-IV acute graft-versus-host disease (GVHD) (Phase 2)(Up to day 100 post-transplant)
- Incidence and severity of grade III-IV acute GVHD (Phase 2)(Up to day 100 post-transplant)
- Incidence and severity of chronic GVHD requiring systemic immunosuppressive therapy (Phase 2)(At 1 year post-transplant)
- Disease response rate (Phase 2)(At day 100 post-transplant)
- Duration of remission from response until documented relapse or progression (Phase 2)(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(Up to day 80 post-transplant)
- Disease-free survival (Phase 2)(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)
- Overall survival (Phase 2)(Up to 2 years post-transplant)
- Proportion of enrolled patients with T-cell non-Hodgkin lymphoma who successfully proceed to allo-HCT(Up to 2 years post-transplant)
- Cumulative incidence of graft-versus-host disease (GVHD)(Up to 1 year post-transplant)
- Incidence of grade II-IV acute GVHD(Up to day 100 post-transplant)
- Incidence of chronic GVHD requiring systemic immunosuppressive therapy(At 1 year post-transplant)
- Disease response rate(At day 100 post-transplant)
- Duration of remission from response until documented relapse or progression(From response until documented relapse or progression, per disease-specific response criteria up to 2 years post-transplant)
- Proportion of donor chimerism ≥ 90% in peripheral blood CD3+ and CD33+ cell lines(Up to day 80 post-transplant)
- Disease-free survival(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)