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

Primary Purpose

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

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Autologous hematopoietic stem cell transplantation (auto-HSCT)
Allogeneic hematopoietic stem cell transplantation (allo-HSCT)
Total lymphoid irradiation (TLI)
Rituximab
Carmustine
Etoposide
Filgrastim
Anti-thymocyte globulin (ATG)
Cyclosporine
Mycophenolate mofetil (MMF)
Cyclophosphamide
Acetaminophen
Diphenhydramine
Hydrocortisone
Methylprednisolone
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma, B-cell

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Stanford University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Auto-HCT followed by Allo-HCT for Poor-risk DLBCL

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
Overall Survival (OS)
To evaluate the overall and transplant related mortality rate, reported as the number of subjects remaining alive 3 years after transplant.

Full Information

First Posted
May 31, 2007
Last Updated
May 11, 2018
Sponsor
Stanford University
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1. Study Identification

Unique Protocol Identification Number
NCT00482053
Brief Title
Phase 2 Poor Risk DLBCL of TLI and ATG Followed by Matched Allogeneic HT as Consolidation to Autologous HCT
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Terminated
Why Stopped
Low accrual
Study Start Date
October 2006 (undefined)
Primary Completion Date
May 2010 (Actual)
Study Completion Date
May 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, B-cell, Lymphoma, Non-Hodgkin, Diffuse Large B-cell Lymphoma (DLBCL), Malignant Lymphoma, Non-Hodgkin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Auto-HCT followed by Allo-HCT for Poor-risk DLBCL
Arm Type
Experimental
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Autologous hematopoietic stem cell transplantation (auto-HSCT)
Other Intervention Name(s)
Autologous peripheral blood progenitor cell (PBPC) transplantation
Intervention Description
Auto-HCT involves an intravenous infusion of a participant's previously collected and frozen white blood cells collected after treatment with mobilizing agents
Intervention Type
Procedure
Intervention Name(s)
Allogeneic hematopoietic stem cell transplantation (allo-HSCT)
Other Intervention Name(s)
Allogeneic peripheral blood progenitor cell (PBPC) transplantation
Intervention Description
Allo-HCT involves an intravenous infusion of a donor's white blood cells collected after treatment with mobilization with filgrastim (G-CSF)
Intervention Type
Procedure
Intervention Name(s)
Total lymphoid irradiation (TLI)
Intervention Description
TLI is administered in 80cGy fractions on Days -11 to Day-7 relative to allo-HSCT
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan, Mabthera
Intervention Description
375 mg/m2 IV days 1 and 7 over 4 to 8 hours
Intervention Type
Drug
Intervention Name(s)
Carmustine
Other Intervention Name(s)
BCNU, BiCNU
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
Eposin, Etopophos, Vepesid, VP-16
Intervention Description
60 mg/kg over 4 hours day -4 and alternatively VP-16 2 Gm/m² may be used (for mobilization)
Intervention Type
Drug
Intervention Name(s)
Filgrastim
Other Intervention Name(s)
Granulocyte colony-stimulating factor (G-CSF, GCSF), Colony-stimulating factor 3 (CSF-3)
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Anti-thymocyte globulin (ATG)
Intervention Description
1.5 mg/kg/day for 5 days
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
Cyclosporin, CSP
Intervention Description
5.0 mg/kg twice daily from day -3 until after day +56
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Other Intervention Name(s)
CellCept
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan, Neosar
Intervention Description
100 mg/kg will be administered over 2 hours on day -2
Intervention Type
Drug
Intervention Name(s)
Acetaminophen
Other Intervention Name(s)
Tylenol
Intervention Description
Pre-medication for rituximab and PBPC infusion. Administered at 650 mg by mouth 1 hour prior to infusion
Intervention Type
Drug
Intervention Name(s)
Diphenhydramine
Other Intervention Name(s)
Benadryl
Intervention Description
Pre-medication for rituximab and PBPC infusion. Administered at 50 mg intravenous 1 hour prior to infusion
Intervention Type
Drug
Intervention Name(s)
Hydrocortisone
Other Intervention Name(s)
Cortef
Intervention Description
Pre-medication for the PBPC infusion. Administered at 100 mg intravenous 1 hour prior to infusion
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Other Intervention Name(s)
Solu-Medrol
Intervention Description
Anti-reaction medication for the ATG infusion. Administered at 1 mg/kg, Day-11 to Day-7
Primary Outcome Measure Information:
Title
Event-free Survival (EFS) Per Protocol
Description
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.
Time Frame
48 months
Secondary Outcome Measure Information:
Title
Median Time to Neutrophil Engraftment After Autologous Transplant
Description
Reported as neutrophil engraftment after autologous transplant, defined as absolute neutrophil count (ANC) > 500/µL, counting from the day of transplant.
Time Frame
within 1 month
Title
Median Time to Platelet Engraftment After Autologous Transplant
Description
Reported as platelet engraftment after autologous transplant, defined as platelet count > 20,000/µL, counting from the day of transplant.
Time Frame
within 1 month
Title
Median Time to Neutrophil Engraftment After Allogeneic Transplant
Description
Reported as neutrophil engraftment after allogeneic transplant, defined as absolute neutrophil count (ANC) > 500/µL, counting from the day of transplant.
Time Frame
within 1 month
Title
Median Time to Platelet Engraftment After Allogeneic Transplant
Description
Reported as platelet engraftment after allogeneic transplant, defined as platelet count > 20,000/µL, counting from the day of transplant.
Time Frame
within 1 month
Title
Incidence of Chronic Graft vs Host Disease (GvHD)
Description
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.
Time Frame
3 years
Title
Overall Survival (OS)
Description
To evaluate the overall and transplant related mortality rate, reported as the number of subjects remaining alive 3 years after transplant.
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wen-Kai Weng
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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