TCR-α/β and CD19 Depleted Stem Cell Grafts From Haplo Donors for HSCT in Relapsed Lymphoma

Study Overview
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Brief Summary
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To determine engraftment of neutrophils and platelets at 28 days following alpha/beta T-cell and CD19 cell depletion using Human Leukocyte Antigen (HLA) haploidentical donors for peripheral blood stem cell transplant in relapsed lymphoma. Assess incidence of acute Graft Versus Host Disease (GVHD), chronic GVHD, graft failure rate, treatment related mortality rate, progression free survival and overall survival of patients. The stem cell product will be processed using an investigational Miltenyi cell selection device/system that removes the alpha/beta T-cells and CD19+ cells, immune system cells that are more likely to cause GVHD.

Official Title
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A Pilot Study to Assess Engraftment Using CliniMACS TCR-α/β and CD19 Depleted Stem Cell Grafts From Haploidentical Donors for Hematopoietic Progenitor Cell Transplantation (HSCT) in Patients With Relapsed Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: Fludarabine Phosphate
* Drug: Mesna
* Drug: Cyclophosphamide
* Radiation: Total nodal irradiation
* Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Procedure: Peripheral Blood Stem Cell Transplantation
* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet one of the following disease criteria within 24 months of registration. Salvage therapy is allowed between the participant meeting one of the below criterion and registration. Participant will be considered eligible regardless of their current disease status (i.e. complete remission, partial remission, stable disease, progressive disease) unless otherwise noted below as long as one of the below criterion has been met within the previous 24 months: Relapsed/refractory Hodgkin lymphoma after autologous stem cell transplantation Relapsed/refractory Hodgkin lymphoma, deemed ineligible for autologous stem cell transplantation due to refractory disease Relapsed/refractory diffuse large B cell lymphoma after autologous stem cell transplantation (history of transformed lymphoma is acceptable). Disease must be in at least complete remission or partial remission with the use of salvage therapy before study treatment commences. Relapsed/refractory diffuse large B cell lymphoma, deemed ineligible for autologous stem cell transplantation due to refractory disease (history of transformed lymphoma is acceptable). Disease must be in at least complete remission or partial remission with the use of salvage therapy before study treatment commences. Relapsed/refractory T cell lymphoma relapsed after at least 1 prior line of therapy Relapsed/refractory follicular lymphoma relapsed after at least 1 prior line of therapy Relapsed/refractory mantle cell lymphoma relapsed after at least 1 prior line of therapy Relapsed/refractory small lymphocytic lymphoma/chronic lymphocytic leukemia relapsed after at least 1 prior line of therapy Relapsed/refractory non-Hodgkin Lymphoma, if not specified above, relapsed after at least 1 prior line of therapy Karnofsky score of 60% or better (Requires occasional assistance, but is able to care for most of his/her needs). Pulmonary: Carbon Monoxide Diffusion Capacity (DLCO) (corrected for hemoglobin) > 40%; and Forced Expiratory Volume (FEV1) > 50% Cardiac: ejection fraction (EF) ≥ 50%. No uncontrolled angina or active cardiac symptoms consistent with congestive heart failure (class III or IV), by the New York Heart Association criteria. No symptomatic ventricular arrhythmias or ECG evidence of active ischemia. No evidence by echocardiography of severe valvular stenosis or regurgitation. Renal: estimated glomerular filtration rate (GFR) by Modification of Diet in Renal Disease (MDRD) formula > 40 mL/min/1.73m2 Women of child bearing potential must have a negative serum or urine pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Voluntary written consent Exclusion Criteria: Active Central nervous system (CNS) lymphoma within two weeks of registration. Patients with a history of CNS involvement must have adequate treatment as defined by at least two negative spinal fluid assessments separated by at least one week. (Otherwise Lumbar Puncture (LP) is not required if no clinical suspicion or evidence of CNS involvement.) Patients who have received cranial radiation therapy must still be eligible to receive total lymphoid irradiation to 7 Gy. New or active infection as determined by fever, unexplained pulmonary infiltrate or sinusitis on radiographic assessment. Infections diagnosed within 4 weeks of registration must be determined to be controlled or resolving prior to treatment. Presence of HIV, or active hepatitis A, B, or C infection Allergy or hypersensitivity to agents used within the treatment protocol. For an indolent lymphoma histology (follicular lymphoma, Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (SLL/CLL)) or mantle cell lymphoma, the patient should not have an HLA-matched sibling, who would be an eligible donor, available. History of prior mediastinal radiation Reported illicit drug use Vulnerable population groups, i.e., prisoners, those lacking consent capacity, non-English speaking, illiterate, pregnant females.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Peripheral Blood Stem Cell Transplant<br>PREPARATIVE REGIMEN: Participants receive fludarabine phosphate IV over approximately 30 minutes on days -5 to -2, and mesna IV over 24 hours and cyclophosphamide IV over approximately 2 hours on days -5 and -4. Participants also undergo total nodal irradiation on day -1. TRANSPLANT: Participants undergo T-Cell Receptor (TCR) alpha-beta/CD19 depleted hematopoietic stem cell transplant on day 0. If the graft contains less than 4 x 10^6 CD34+ cells/kg participant body weight (BW), patients may receive a second graft on day 1. GVHD PROPHYLAXIS: Participants receive mycophenolate mofetil orally twice a day (PO BID) on days -1 to 30, tacrolimus PO or IV on days 2-180 with a taper beginning on day 90 (given only if graft TCR alpha-beta+ cell content is over 1 x 10^5 cells/kg ideal BW of the patient), and rituximab IV on day 2 (given only if graft B cell content exceeds 1 x 10^5 cells/kg ideal BW of the participant). | Drug: Fludarabine Phosphate<br>* Fludarabine will be administered by IV over approximately 30 minutes for 4 days.<br>Drug: Mesna<br>* Given IV over 24 hours starting prior to cyclophosphamide<br>Drug: Cyclophosphamide<br>* Given IV for 2 days<br>Radiation: Total nodal irradiation<br>* Undergo total lymphoid irradiation<br>Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation<br>* Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant<br>Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant<br>* Other names: HSCT;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo TCR alpha-beta/CD19-depleted hematopoietic stem cell transplant<br>Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Drug: Tacrolimus<br>* Given PO or IV ONLY if graft cell content is over 1 x 10^5 cells/kg ideal BW of the patient<br>Biological: Rituximab<br>* Given IV ONLY if graft B cell content exceeds 1 x 10^5 cells/kg ideal BW of the patient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Absolute Neutrophil Count >= 500/Mcl for 3 Consecutive Measurements on Different Days and Platelet Count > 20,000/mm^3 With no Platelet Transfusions in the Preceding 7 Days | To determine engraftment of neutrophils and platelets at 28 days following alpha/beta T-cell depletion using Human Leukocyte Antigen (HLA) haploidentical donors for stem cell transplant in relapsed lymphoma. | At day 28 after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade III-IV Acute GVHD as Determined by International Bone Marrow Transplant Registry (IBMTR) Severity Index Criteria | The number of participants with grade III - IV acute Graft versus host disease (GVHD) by Day +100 is reported. | Day +100 | 
| Number of Participants With Severe Chronic GVHD | The number of participants with severe chronic GVHD by Day +180 will be reported. | Day +180 | 
| Number of Participants With Graft Failure | Graft failure - defined as < 5% donor chimerism in the CD3 and/or CD33 selected cell populations at any time during the study follow up period once initial engraftment has been achieved. | Up to 2 years after graft | 
| Number of Participants With Treatment-related Mortality | Treatment-related mortality is defined as death from any cause other than disease progression. | Up to 2 years after graft | 
| Progression-free Survival | Progression-free survival will be analyzed as time before any progression by either Positron Emission Tomography/Computed Tomography (PET/CT) or bone marrow, | Median follow up of 1689 days | 
| Overall Survival (OS) |  | Median follow up of 1689 days |