Phase 2 Poor Risk DLBCL of TLI and ATG Followed by Matched Allogeneic HT as Consolidation to Autologous HCT

Study Overview
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Brief Summary
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The purpose of this study is to determine if double autologous then allogeneic hematopoietic cell transplant may offer an improved treatment option for patients with relapsed diffuse large B-cell lymphoma (DLBCL) who are not likely to be cured by the conventional transplantation regimen.

Detailed Description
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This study tests a tandem transplant approach that starts with transplantation of the participant's own hematopoietic (blood) cells, eg, autologous hematopoietic cell transplant (auto-HCT) as preparation for an subsequent matched-donor allogeneic HCT (allo-HCT). Participants will be have progenitor cells (stem cells) mobilized into the peripheral blood with rituximab, chemotherapy (cyclophosphamide or etoposide), and filgrastim (G-CSF); undergo apheresis to collect autologous peripheral blood stem cells (PBSC, aka hematopoietic cells); and be re-infused with ≥ 3 x 10e6 CD34+ cells/kg (auto-HCT). Subsequently, participants will receive therapeutic, non-myeloablative chemotherapy (carmustine + cyclophosphamide + etoposide), then transplant conditioning [total lymphoid irradiation (TLI) + anti-thymocyte globulin (ATG)] followed by ≥ 2 x 10e6 CD34+ cells/kg allogeneic PBSC obtained from a human leukocyte antigen (HLA)-matched or HLA single allele / antigen-mismatched donor (allo-HCT). Donors will be mobilized with 16 µg/kg filgrastim. Participant allo-HCT transplant is to occur within 150 days of auto-HCT. Post-allo-HCT infusion treatment includes cyclosporine and mycophenolate mofetil (MMF) Subject's participation ends if a suitable matched donor is not identified within the 150 days. Pre-medication treatments administered during this study may include acetaminophen; diphenhydramine; hydrocortisone; and methylprednisolone.

Official Title
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A Phase 2 Study in Poor Risk Diffuse Large B-cell Lymphoma of Total Lymphoid Irradiation & Antithymocyte Globulin Followed by Matched Allogeneic Hematopoietic Transplantation as Consolidation to Autologous Hematopoietic Cell Transplantation

Conditions
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Lymphoma, B-cell, Lymphoma, Non-Hodgkin, Diffuse Large B-cell Lymphoma (DLBCL), Malignant Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Procedure: Autologous hematopoietic stem cell transplantation (auto-HSCT)
* Procedure: Allogeneic hematopoietic stem cell transplantation (allo-HSCT)
* Procedure: Total lymphoid irradiation (TLI)
* Drug: Rituximab
* Drug: Carmustine
* Drug: Etoposide
* Drug: Filgrastim
* Drug: Anti-thymocyte globulin (ATG)
* Drug: Cyclosporine
* Drug: Mycophenolate mofetil (MMF)
* Drug: Cyclophosphamide
* Drug: Acetaminophen
* Drug: Diphenhydramine
* Drug: Hydrocortisone
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Age 18 to 70 years. Histologically-proven diffuse large B-cell lymphoma (DLBCL) by the World Health Organization (WHO) classification. Relapse after achieving initial remission or failure to achieve initial remission. Patients with residual radiographic abnormalities after primary therapy are eligible if abnormalities are postive by fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET). Receipt of 2 cycles of second-line therapy and FDG-PET positive per Stanford (central) review. FDG-PET to be done 2 weeks after cycle 2 of second line chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status < 2 Matched related or unrelated donor identified and available Bone marrow biopsy and cytogenetic analysis within 8 weeks of registration Pretreatment serum bilirubin < 2 x the institutional upper limit of normal (ULN) Serum creatinine < 2 x the institutional ULN and measured or estimated creatinine clearance > 60 mL/min by the following formula (all tests must be performed within 28 days prior to registration): Estimated Creatinine Clearance = (140 age) x weight (kg) x 0.85 if female 72 x serum creatinine (mg/dL). EKG within 42 days prior to registration with no significant abnormalities suggestive of active cardiac disease Patients must have a radionuclide ejection fraction within 42 days of registration. If the ejection fraction is < 40%, the patient will not be eligible. If the ejection fraction is 40-50%, the patient will have a cardiology consult. Corrected diffusion capacity > 55%. Sexually active males are advised to use an accepted and effective method of birth control Women of child-bearing potential are advised to use an accepted and effective method of birth control Patients must sign and give written informed consent in accordance with institutional and federal guidelines. Patients must be informed of the investigational nature of this study. EXCLUSION CRITERIA Known allergy to etoposide or a history of Grade 3 hemorrhagic cystitis with cyclophosphamide Greater than Grade 2 sensory or motor peripheral neuropathy from prior vinca alkaloid use Requiring therapy for coronary artery disease, cardiomyopathy, dysrhythmia, or congestive heart failure Known to be human immunodeficiency virus (HIV)-positive. The antibody test for HIV must be performed within 42 days of registration. Prior chemotherapy other than corticosteroids administered within 2 weeks of the initiation of protocol therapy. Prior malignancy, except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or other cancer for which the patients has been disease-free for five years. Prior diagnosis of non-Hodgkin's lymphoma Active infection requiring oral or intravenous antibiotics Prior autologous or allogeneic hematopoietic cell transplantation Prior radioimmunotherapy Pregnant Lactating DONOR ELIGIBILITY Related or unrelated HLA-identical donors who are in good health and have no contra-indication to donation No contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by G-CSF at a dose of 16 µg/kg of body weight. Donors will be evaluated with a full history and physical examination. Virology testing including HIV; cytomegalovirus (CMV); Epstein-Barr virus (EBV); human T-lymphotropic virus (HTLV); rapid plasma reagin (RPR); Hepatitis A, B and C be performed within 30 days of donation. Prospective donors will be screened for CMV seroreactivity and seronegative donors will be utilized if available. If more than one human leukocyte antigen (HLA)-matched related donor exists, then the donor will be selected on the basis of CD31 allotype.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Auto-HCT followed by Allo-HCT for Poor-risk DLBCL<br>Participants will have peripheral blood stem cells (PBSC, aka progenitor / stem cells) mobilized to peripheral blood with rituximab, chemotherapy (cyclophosphamide or etoposide), and filgrastim; undergo apheresis to collect (self/autologous PBSC), and receive carmustine, etoposide, and cyclophosphamide as conditioning for PBSC infusion as a hematopoietic cell transplant (auto-HCT). Then participants will receive allogeneic HCT (allo-HCT) transplant conditioning [total lymphoid irradiation (TLI) + anti-thymocyte globulin (ATG)] followed by allogenic PBSC (allo-HCT) obtained from a human leukocyte antigen (HLA)-matched or single mismatch filgrastim-mobilized donor. Participant allo-HCT transplant is to occur within 150 days of auto-HCT. Post-allo-HCT treatment includes cyclosporine + mycophenolate mofetil (MMF). Subject's participation ends if donor is not identified within 150 days. Pre-medication includes acetaminophen; diphenhydramine; hydrocortisone; & methylprednisolone. | Procedure: Autologous hematopoietic stem cell transplantation (auto-HSCT)<br>* Auto-HCT involves an intravenous infusion of a participant's previously collected and frozen white blood cells collected after treatment with mobilizing agents<br>* Other names: Autologous peripheral blood progenitor cell (PBPC) transplantation;Procedure: Allogeneic hematopoietic stem cell transplantation (allo-HSCT)<br>* Allo-HCT involves an intravenous infusion of a donor's white blood cells collected after treatment with mobilization with filgrastim (G-CSF)<br>* Other names: Allogeneic peripheral blood progenitor cell (PBPC) transplantation;Procedure: Total lymphoid irradiation (TLI)<br>* TLI is administered in 80cGy fractions on Days -11 to Day-7 relative to allo-HSCT<br>Drug: Rituximab<br>* 375 mg/m2 IV days 1 and 7 over 4 to 8 hours<br>* Other names: Mabthera;Drug: Carmustine<br>* Based on body weight, unless its more than 15 kg greater than the idal body 15mg/kg (max dose 550 mg/m2) day -6 over 2 hours. Males IBW = 50 kg + 2.3 kg/inch over 5 feet Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet Adjusted IBW = IBW + 50% (actual weight - IBW)<br>* Other names: BiCNU;Drug: Etoposide<br>* 60 mg/kg over 4 hours day -4 and alternatively VP-16 2 Gm/m² may be used (for mobilization)<br>* Other names: VP-16;Drug: Filgrastim<br>* 10 µg/kg/day subcutaneous starting Day 9 until last day of apheresis. 5 ug/kg actual body weight per day will be started at Day +6 after allo-HCT until hematologic recovery<br>* Other names: Colony-stimulating factor 3 (CSF-3);Drug: Anti-thymocyte globulin (ATG)<br>* 1.5 mg/kg/day for 5 days<br>Drug: Cyclosporine<br>* 5.0 mg/kg twice daily from day -3 until after day +56<br>* Other names: CSP;Drug: Mycophenolate mofetil (MMF)<br>* 250 mg (total) twice daily, oral 15 mg/kg po on day 0, at 5-10 hours after mobilized PBPC infusion is complete. On day +1 MMF is taken at 15 mg/kg po b.i.d. (30 mg/kg/day) if transplantation was using a matched related donor and 15 mg/kg po t.i.d if from a matched unrelated donor or a one antigen mismatched donor.<br>* Other names: CellCept;Drug: Cyclophosphamide<br>* 100 mg/kg will be administered over 2 hours on day -2<br>* Other names: Neosar;Drug: Acetaminophen<br>* Pre-medication for rituximab and PBPC infusion. Administered at 650 mg by mouth 1 hour prior to infusion<br>* Other names: Tylenol;Drug: Diphenhydramine<br>* Pre-medication for rituximab and PBPC infusion. Administered at 50 mg intravenous 1 hour prior to infusion<br>* Other names: Benadryl;Drug: Hydrocortisone<br>* Pre-medication for the PBPC infusion. Administered at 100 mg intravenous 1 hour prior to infusion<br>* Other names: Cortef;Drug: Methylprednisolone<br>* Anti-reaction medication for the ATG infusion. Administered at 1 mg/kg, Day-11 to Day-7<br>* Other names: Solu-Medrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) Per Protocol | Event-free survival (EFS) through 4 years, as assessed in participants with poor-risk recurrent or primary refractory DLBCL treated with TLI and ATG followed by matched allogeneic hematopoietic cell transplantation as a consolidation to HCT. Event is defined as tumor progression or death. | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Neutrophil Engraftment After Autologous Transplant | Reported as neutrophil engraftment after autologous transplant, defined as absolute neutrophil count (ANC) > 500/µL, counting from the day of transplant. | within 1 month | 
| Median Time to Platelet Engraftment After Autologous Transplant | Reported as platelet engraftment after autologous transplant, defined as platelet count > 20,000/µL, counting from the day of transplant. | within 1 month | 
| Median Time to Neutrophil Engraftment After Allogeneic Transplant | Reported as neutrophil engraftment after allogeneic transplant, defined as absolute neutrophil count (ANC) > 500/µL, counting from the day of transplant. | within 1 month | 
| Median Time to Platelet Engraftment After Allogeneic Transplant | Reported as platelet engraftment after allogeneic transplant, defined as platelet count > 20,000/µL, counting from the day of transplant. | within 1 month | 
| Incidence of Chronic Graft vs Host Disease (GvHD) | The incidence of chronic graft vs host disease (GvHD) is reported as any events within 3 years. Note that GvHD was assessed per investigator judgement. There was no protocol-specified criteria of GvHD. | 3 years | 
| Overall Survival (OS) | To evaluate the overall and transplant related mortality rate, reported as the number of subjects remaining alive 3 years after transplant. | 3 years |