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

NCT ID: NCT00482053

Last Updated: 2018-05-14

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-10-31
• Study Completion Date: 2010-05-31

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

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.

Group Type: EXPERIMENTAL

Autologous hematopoietic stem cell transplantation (auto-HSCT)

Intervention Type: PROCEDURE

Auto-HCT involves an intravenous infusion of a participant's previously collected and frozen white blood cells collected after treatment with mobilizing agents

Allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Intervention Type: PROCEDURE

Allo-HCT involves an intravenous infusion of a donor's white blood cells collected after treatment with mobilization with filgrastim (G-CSF)

Total lymphoid irradiation (TLI)

Intervention Type: PROCEDURE

TLI is administered in 80cGy fractions on Days -11 to Day-7 relative to allo-HSCT

Rituximab

Intervention Type: DRUG

375 mg/m2 IV days 1 and 7 over 4 to 8 hours

Carmustine

Intervention Type: DRUG

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)

Etoposide

Intervention Type: DRUG

60 mg/kg over 4 hours day -4 and alternatively VP-16 2 Gm/m² may be used (for mobilization)

Filgrastim

Intervention Type: DRUG

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

Anti-thymocyte globulin (ATG)

Intervention Type: DRUG

1.5 mg/kg/day for 5 days

Cyclosporine

Intervention Type: DRUG

5.0 mg/kg twice daily from day -3 until after day +56

Mycophenolate mofetil (MMF)

Intervention Type: DRUG

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.

Cyclophosphamide

Intervention Type: DRUG

100 mg/kg will be administered over 2 hours on day -2

Acetaminophen

Intervention Type: DRUG

Pre-medication for rituximab and PBPC infusion. Administered at 650 mg by mouth 1 hour prior to infusion

Diphenhydramine

Intervention Type: DRUG

Pre-medication for rituximab and PBPC infusion. Administered at 50 mg intravenous 1 hour prior to infusion

Hydrocortisone

Intervention Type: DRUG

Pre-medication for the PBPC infusion. Administered at 100 mg intravenous 1 hour prior to infusion

Methylprednisolone

Intervention Type: DRUG

Anti-reaction medication for the ATG infusion. Administered at 1 mg/kg, Day-11 to Day-7

Interventions

Autologous hematopoietic stem cell transplantation (auto-HSCT)

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

Allogeneic hematopoietic stem cell transplantation (allo-HSCT)

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

Total lymphoid irradiation (TLI)

TLI is administered in 80cGy fractions on Days -11 to Day-7 relative to allo-HSCT

Intervention Type: PROCEDURE

Rituximab

375 mg/m2 IV days 1 and 7 over 4 to 8 hours

Intervention Type: DRUG

Carmustine

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

Etoposide

60 mg/kg over 4 hours day -4 and alternatively VP-16 2 Gm/m² may be used (for mobilization)

Intervention Type: DRUG

Filgrastim

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

Anti-thymocyte globulin (ATG)

1.5 mg/kg/day for 5 days

Intervention Type: DRUG

Cyclosporine

5.0 mg/kg twice daily from day -3 until after day +56

Intervention Type: DRUG

Mycophenolate mofetil (MMF)

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

Cyclophosphamide

100 mg/kg will be administered over 2 hours on day -2

Intervention Type: DRUG

Acetaminophen

Pre-medication for rituximab and PBPC infusion. Administered at 650 mg by mouth 1 hour prior to infusion

Intervention Type: DRUG

Diphenhydramine

Pre-medication for rituximab and PBPC infusion. Administered at 50 mg intravenous 1 hour prior to infusion

Intervention Type: DRUG

Hydrocortisone

Pre-medication for the PBPC infusion. Administered at 100 mg intravenous 1 hour prior to infusion

Intervention Type: DRUG

Methylprednisolone

Anti-reaction medication for the ATG infusion. Administered at 1 mg/kg, Day-11 to Day-7

Intervention Type: DRUG

Other Intervention Names

Autologous peripheral blood progenitor cell (PBPC) transplantation; Allogeneic peripheral blood progenitor cell (PBPC) transplantation; Rituxan; Mabthera; BCNU; BiCNU; Eposin; Etopophos; Vepesid; VP-16; Granulocyte colony-stimulating factor (G-CSF, GCSF); Colony-stimulating factor 3 (CSF-3); Cyclosporin; CSP; CellCept; Cytoxan; Neosar; Tylenol; Benadryl; Cortef; Solu-Medrol

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanford University

OTHER

Sponsor Role: lead

Responsible Party

Wen-Kai Weng

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wen-Kai Weng

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

Stanford University School of Medicine

Stanford, California, United States

Countries

United States

Other Identifiers

97355

Identifier Type: OTHER

Identifier Source: secondary_id

BMT186

Identifier Type: OTHER

Identifier Source: secondary_id

IRB-06703

Identifier Type: -

Identifier Source: org_study_id