Reduced Intensity Conditioning Before Partially Matched Donor Stem Cell Transplant in Treating Patients With Advanced Cutaneous T Cell Lymphoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and the best dose of donor lymphocyte infusion when given together with reduced intensity conditioning regimen before partially matched donor stem cell transplant in treating patients with stage IIB-IV mycosis fungoides or Sezary syndrome. Giving chemotherapy and low-dose total-body irradiation followed by high-dose cyclophosphamide before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Removing the T-cells from the donor cells and giving them before transplant may stop this from happening. Additionally, giving tacrolimus and mycophenolate mofetil before and after transplant may also stop this from happening.

Detailed Description
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PRIMARY OBJECTVES: I. To evaluate regimen related toxicity, engraftment and graft versus host disease (GVHD) in the first 100 days with new reduced intensity haploidentical regimen protocol, including fludarabine (fludarabine phosphate), low dose total body irradiation, and cyclophosphamide. II. To determine an effective donor lymphocyte infusion (DLI) dose that provides successful engraftment without causing GVHD. SECONDARY OBJECTIVES: I. To assess myeloid and lymphoid engraftment rates of patients undergoing treatment on this regimen. II. To determine the incidence and severity of GVHD in patients undergoing treatment on this regimen using a combination of tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis. III. To examine progression free survival and overall survival in patients with cytotoxic T-cell lymphoma (CTCL) undergoing treatment on this regimen. IV. To assess the pace of lymphoid recovery in this patient population. OUTLINE: This is a phase I, dose-escalation study of DLI. REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -11 to -8 and undergo total body irradiation twice daily (BID) on day -7. Patients also receive donor cluster of differentiation (CD)3+ enriched T lymphocyte infusion on day -6 and high-dose cyclophosphamide IV over 2 hours on days -3 to -2. TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0. GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV with taper (drug wean) by day 60 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD. After completion of treatment, patients are followed up periodically.

Official Title
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A Two-Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Cutaneous T Cell Lymphoma

Conditions
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Cutaneous T-Cell Non-Hodgkin Lymphoma, Recurrent Mycosis Fungoides and Sezary Syndrome, Stage IIB Mycosis Fungoides and Sezary Syndrome, Stage IIIA Mycosis Fungoides and Sezary Syndrome, Stage IIIB Mycosis Fungoides and Sezary Syndrome, Stage IVA Mycosis Fungoides and Sezary Syndrome, Stage IVB Mycosis Fungoides and Sezary Syndrome

Intervention / Treatment
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* Drug: Fludarabine
* Radiation: Total-Body Irradiation
* Biological: T Cell-Depleted Donor Lymphocyte Infusion
* Drug: Cyclophosphamide
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Procedure: Peripheral Blood Stem Cell Transplantation
* Drug: Mycophenolate mofetil
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage IIB-IV mycosis fungoides and sezary syndrome who have failed at least one standard systemic therapy or are not candidates for standard therapy. Patient should have a responsive skin disease including complete remission (CR) and partial remission (PR) (close to CR; 75%-99% clearance of skin disease from baseline without new tumors (T3) in patients with T1, T2 or T4 only skin disease) and should not have visceral organ or lymph node involvement prior to transplantation. Patients must have a related donor who is a two or more allele mismatch at the HLA-A; B; C; DR and DQ loci. Patients who have sibling donors with a one antigen mismatch due to recombination will not be enrolled in this protocol. Patients must have adequate organ function: Left Ventricular Ejection Fraction (LVEF) of >50% Carbon Monoxide Diffusing Capacity (DLCO) >50% of predicted corrected for hemoglobin Adequate liver function as defined by a serum bilirubin <2.0 (unless hemolysis or Gilbert disease), Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) < 2.5 X upper limit of normal Creatinine clearance of > 60 ml/min Performance status > 80% (Karnofsky) Hematopoietic Cell Transplantation Specific Comorbidity Index (HCT-CI) <5 for age < 65, HCT-CI <4 for age >65 Patients must be willing to use contraception if they have childbearing potential Able to give informed consent, or their legally authorized representative can give informed consent. Exclusion Criteria: Performance status of < 80% (Karnofsky) HIV positive Active involvement of the central nervous system with malignancy Psychiatric disorder that would preclude patients from signing an informed consent Pregnancy, or unwillingness to use contraception if they are have childbearing potential. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder or complications there from. Patients who have received alemtuzumab within 8 weeks of transplant admission, or who have recently received horse or rabbit anti-thymocyte globulin (ATG) and have ATG levels of > 2 μgm/ml. Patients who cannot receive cyclophosphamide Patients with evidence of another malignancy (exclusive of a skin cancer that requires only local treatment); Patients with prior malignancies diagnosed> 5 years ago without evidence of disease are eligible. Patients with prior malignancy treated < 5 years ago but have a life expectancy of > 5 years for that malignancy are eligible. Uncontrolled active infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced Intensity Conditioning, DLI, PBSCT<br>REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -11 to -8 and undergo total body irradiation BID on day -7. Patients also receive donor CD3+ enriched T lymphocyte infusion on day -6 and high-dose cyclophosphamide IV over 2 hours on days -3 to -2. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV with taper (drug wean) by day 60 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD. | Drug: Fludarabine<br>* Given IV<br>* Other names: Fludara;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>Biological: T Cell-Depleted Donor Lymphocyte Infusion<br>* Undergo donor CD3+ enriched T lymphocyte infusion<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: CP;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSC transplant<br>Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>Drug: Mycophenolate mofetil<br>* Given IV<br>* Other names: MMF;Drug: Tacrolimus<br>* Given IV<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of regimen-related toxicities | Estimate of dose-specific rates of toxicity will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling. | Up to 100 days post-transplant | 
| Rate for hematopoietic engraftment | Estimate of dose-specific rate for engraftment will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling. | Up to 100 days post-transplant | 
| Rate for immune reconstitution | Estimate of dose-specific rate for immune reconstitution will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling. | Up to 100 days post-transplant | 
| Incidence of GVHD |  | Up to 100 days post-transplant | 
| Maximum tolerated dose of DLI, determined according to dose limiting toxicities |  | day -4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myeloid engraftment rate |  | Up to 6 months post-transplant | 
| Lymphoid engraftment rate |  | Up to 6 months post-transplant | 
| Incidence of GVHD using tacrolimus and mycophenolate mofetil prophylaxis |  | Up to 6 months post-transplant | 
| Progression free survival | Progression free survival will be estimated by the Kaplan-Meier method. | Up to 6 months post-transplant | 
| Overall survival (OS) | OS will be estimated by the Kaplan-Meier method. | Up to 6 months post-transplant | 
| Rate of lymphoid recovery |  | Up to 6 months post-transplant | 
| Incidence of adverse events | All estimates of dose-specific rates (e.g., toxicity) will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling. | Up to 6 months |