Clinical trial NCT00482053: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lymphoma, B-cell
Lymphoma, Non-Hodgkin
Diffuse Large B-cell Lymphoma (DLBCL)
Malignant Lymphoma, Non-Hodgkin
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2007-06-04
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Event-free Survival (EFS) Per Protocol
timeFrame: 48 months
Secondary outcomes:
measure: Median Time to Neutrophil Engraftment After Autologous Transplant
timeFrame: within 1 month
measure: Median Time to Platelet Engraftment After Autologous Transplant
timeFrame: within 1 month
measure: Median Time to Neutrophil Engraftment After Allogeneic Transplant
timeFrame: within 1 month
measure: Median Time to Platelet Engraftment After Allogeneic Transplant
timeFrame: within 1 month
measure: Incidence of Chronic Graft vs Host Disease (GvHD)
timeFrame: 3 years
measure: Overall Survival (OS)
timeFrame: 3 years
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: Wen-Kai Weng
role: PRINCIPAL_INVESTIGATOR
References: