Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using TLI & ATG

Study Overview
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Brief Summary
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To evaluate the toxicity and tolerability of this tandem autologous/allogeneic transplant approach for patients with advanced stage multiple myeloma.

Detailed Description
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Development of cell-based immunotherapy from allogeneic hematopoietic cell transplantation (HCT) is dependent upon stable T-cell engraftment and the success of this therapeutic approach is likely to be greatest when directed against a minimal rather than gross tumor burden. To this end, tandem transplants with high dose therapy and autologous hematopoietic cell transplantation (AHCT) for tumor cytoreduction followed by non-myeloablative allotransplant have been conducted. In myeloma, this tandem approach results in greater efficacy compared to conventional AHCT.

Official Title
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A Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Antithymocyte Globulin (ATG) in Multiple Myeloma Patients

Conditions
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Transplantation, Homologous, Transplantation, Autologous, Multiple Myeloma, Blood and Marrow Transplant (BMT)

Intervention / Treatment
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* Procedure: Autologous peripheral blood stem cells (auto-PBSC) transplantation
* Procedure: Allogeneic peripheral blood stem cells (allo-PBSC) transplantation
* Drug: Filgrastim
* Drug: Cyclophosphamide
* Drug: Melphalan
* Drug: Cyclosporine
* Radiation: Total lymphoid irradiation
* Biological: Rabbit anti-thymocyte globulin
* Drug: Mycophenolate Mofetil 250mg
* Drug: Solumedrol
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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PARTICIPANT INCLUSION CRITERIA Stage II-III multiple myeloma or have progression after initial treatment of Stage I disease (Durie Salmon Staging). Patients with plasma cell leukemia are also included. Multiple myeloma / plasma cell leukemia diagnosis confirmed by pathology reviewed at Stanford University Medical Center. 18 to ≤ 75 years of age Karnofsky Performance Status > 70%. Corrected Carbon monoxide diffusing capacity (Dlco) > 60% Left ventricle ejection fraction (LVEF) > 50%. Alanine aminotransferase (ALT) ≤ 2 x normal Aspartate aminotransferase (AST) ≤ 2 x normal Total bilirubin ≤ 2 mg/dL, unless hemolysis or Gilbert's disease. Estimated creatinine clearance > 50 mL/min. Identified related or unrelated Human leukocyte antigen (HLA)-identical donor or donor with one antigen/allele mismatch in (HLA-A, B, C or DRB1). Signed informed consent. DONOR INCLUSION CRITERIA At least 17 years of age HIV-seronegative Must be capable of giving signed, informed consent No contraindication to the administration of filgrastim Willing to have a central venous catheter placed for apheresis if peripheral veins are inadequate PARTICIPANT EXCLUSION CRITERIA Prior allogeneic hematopoietic cell transplantation Uncontrolled active infection Uncontrolled congestive heart failure or angina HIV-positive Pregnant or nursing DONOR EXCLUSION CRITERIA Serious medical or psychological illness Pregnant or lactating Prior malignancies within the last 5 years except for non-melanoma skin cancers

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: Autologous-Allogeneic Peripheral Blood Stem Cell Transplant<br>Study treatment is a high-dose sequential chemotherapy approach to hematopoietic stem cell (HSC) transplant that uses an autologous peripheral blood stem cell (auto-PBSC) transplant followed by allogeneic peripheral blood stem cell (allo-PBSC) transplant to evaluate improved graft vs host disease (GvHD) control. Participant auto-PBSC are mobilized with cyclophosphamide (also to provide cytoreduction) and filgrastim, followed by melphalan as an auto-PBSC conditioning agent, then auto-PBSC infusion. For the allo-PBSC transplant, donors are mobilized with filgrastim, and participants receive a regimen of total lymphoid irradiation and anti-thymocyte globulin (TLI/ATG), followed by infusion of donor allo-PBSC. Solumedrol, diphenhydramine, acetaminophen, and hydrocortisone are administered as premedications, and rabbit anti-thymocyte globulin (ATG) plus mycophenolate mofetil (MMF) are administered for post-allo-PBSC immunosuppression. | Procedure: Autologous peripheral blood stem cells (auto-PBSC) transplantation<br>* Auto-PBSC ≥ 2 to 3 x 10e6 CD34+ cells/kg are intravenously (IV) infused as part of the combination stem cell therapy. and allogeneic stem cells are administered intravenous (IV) infusion to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective<br>* Other names: Autologous peripheral blood progenitor cells (auto-PBPC) transplantation;Procedure: Allogeneic peripheral blood stem cells (allo-PBSC) transplantation<br>* Allo-PBSC (target collection ≥ 5 x 10e6 CD34+ cells/kg) are intravenously (IV) infused as part of the combination stem cell therapy.<br>* Other names: Allogeneic peripheral blood progenitor cells (allo-PBPC) transplantation;Drug: Filgrastim<br>* Filgrastim is administered subcutaneously (SC) at 10 µg/kg/day for auto-PBSC mobilization starting day 2 of mobilization until the last day of apheresis. Filgrastim is administered SC at 5 µg/kg/day from Day 6 after auto-PBSC infusion to hematologic recovery. Filgrastim is administered SC at 16 µg/kg/day for donor allo-PBSC mobilization at from Day - 4 to Day 0, prior to allo-PBSC collection.<br>* Other names: r-metHuG-CSF;Drug: Cyclophosphamide<br>* Cyclophosphamide is administered intravenously (IV) at 4 g/m2 on Day 1 of the auto-PBSC mobilization regimen.<br>* Other names: CSP;Drug: Melphalan<br>* Melphalan is administered after CSP at 200 mg/m2 intravenously (IV) on Day -2 before auto-PBSC infusion.<br>* Other names: L-sarcolysine;Drug: Cyclosporine<br>* Cyclosporine is administered by mouth (PO) for allo-PBSC graft vs host disease (GvHD) prophylaxis at 5 mg/kg from Day -3 through Bay +56. Tacrolimus may substituted.<br>* Other names: CSP;Radiation: Total lymphoid irradiation<br>* Total lymphoid irradiation is administered at 80 centigrey (cGy) on Day -11 to -7; and Day -4 to -2 before alllo-PBSC infusion. TLI is also administered at 80 centigrey (cGy) x 2 on Day -1 before alllo-PBSC infusion.<br>* Other names: TLI;Biological: Rabbit anti-thymocyte globulin<br>* ATG 1.5 mg/kg is administered intravenously (IV) on Day -11 to -7 before allo-PBSC infusion.<br>* Other names: ATG;Drug: Mycophenolate Mofetil 250mg<br>* MMF is administered at 15 mg/kg 3x/day by mouth (PO) after allo-PBSC through Day 40, followed by 10% dose reduction weekly (dose taper) through day 96, and adjusted if there is evidence of MMF-related GI toxicity or excessive myelosuppression<br>* Other names: MMF;Drug: Solumedrol<br>* Solumedrol 1 mg/kg is administered intravenously (IV) on Day -11 to -7 as a premedication for ATG and allo-PBSC infusion<br>* Other names: Soludecadron;Drug: Diphenhydramine<br>* Diphenhydramine 25 to 50 mg is administered as a premedication for the ATG; allo-PBSC; and DLI infusions.<br>* Other names: Benadryl;Drug: Acetaminophen<br>* Acetaminophen 650 mg is administered as a premedication for the ATG and allo-PBSC infusions.<br>* Other names: Tylenol;Drug: Hydrocortisone<br>* Hydrocortisone 100 mg is administered intravenously (IV) is a premedication for the allo-PBSC and DLI infusions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Graft Versus Host Disease (GvHD) | To evaluate the incidence acute GvHD of this tandem autologous/allogeneic transplant setting | 2 years after the last participant is enrolled. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Engraftment After Auto-PBSC Transplant | Engraftment is assessed as: Neutrophil engraftment is > 0.5 x 10⁹/L after cytopenia Platelet engraftment is > 20 x 10⁹/L after cytopenia | 1 month | 
| Median Time to Engraftment After Allo-PBSC Transplant | Engraftment is assessed as: Neutrophil engraftment is > 0.5 x 10⁹/L after cytopenia Platelet engraftment is > 20 x 10⁹/L after cytopenia | 1 month | 
| Overall Response Rate (ORR) | Overall response rate (ORR) = Complete Response Rate (CRR) + Partial Response Rate (PRR) | 1 year | 
| Complete Response Rate (CRR) | Complete response rate (CRR) was assessed as all of: Negative immunoflixation on the serum and urine Disappearance of any soft tissue plasmacytomas < 5% plasma cells in bone marrow | 1 year | 
| Partial Response Rate (PRR) | Partial response rate (PRR) was assessed as > 50% reduction in serum M-protein plus urine M-protein reduction by 90% or < 200 mg/24 hr If serum M-protein is not measurable, then > 50% reduction in the involved serum free light chain If involved serum free light chain is not measurable, then > 50% reduction in the bone marrow plasma cell percentage + > 50% reduction in the size of any soft tissue plasmacytoma. | 1 year | 
| Event-free Survival (EFS) | To evaluate the graft versus myeloma effect by monitoring rate of event-free survival (EFS) | 2 years after the last participant is enrolled | 
| Overall Survival (OS) | To evaluate the graft versus myeloma effect by monitoring rate of overall survival (OS) | 2 years after the last participant is enrolled |