Autologous or Donor Stem Cell Transplantation in Treating Patients With Recurrent Non-Hodgkin's Lymphoma (BMT CTN 0202)

NCT ID: NCT00096460

Last Updated: 2023-01-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-08-31
• Study Completion Date: 2009-03-31

Brief Summary

This study is designed as a Phase II/III, multi-center trial, comparing two transplant strategies to determine whether non-myeloablative allogeneic Hematopoietic Stem Cell Transplantation (HSCT) will improve long-term progression-free survival compared to autologous HSCT. Recipients will be biologically assigned to the appropriate treatment arm depending on the availability of a Human Leukocyte Antigen (HLA) matched sibling.

Detailed Description

BACKGROUND:

Although patients with follicular non-Hodgkin's lymphoma (NHL) typically experience a relatively indolent course, the disease is rarely curable with conventional chemotherapy. Patients with follicular NHL are usually treated only when symptoms require palliation or if bulky disease exists since no survival advantage has been shown as compared to administering conventional treatment at initial diagnosis. While most patients achieve a remission with initial chemotherapy, a continuous pattern of relapse occurs, resulting in progressively shorter remission durations. Additionally, the increased response rates conferred by anthracycline-containing regimens have not translated into improved survival and thus the median survival time of 6 to 10 years has not been significantly impacted over the last decade.

DESIGN NARRATIVE:

The overall study design is a comparison of two treatment arms determined by biologic assignment, based on the availability of an HLA-matched sibling, in patients diagnosed with relapsed follicular non-Hodgkin's lymphoma. Patients without an HLA-matched sibling will receive an autologous HSCT. Patients with an HLA-matched sibling will receive a non-myeloablative allogeneic HSCT.

The overall study design is that of biologic assignment, based on the availability of an HLA-matched sibling, to one of two strategies to improve the outcome for follicular lymphoma patients with chemosensitive disease. All patients will undergo cytoreduction with cyclophosphamide 4 gm/m^2 and rituximab 375 mg/m^2 x 2 doses. Rituximab will be given in two doses, approximately 1 week apart, with the cyclophosphamide administered the day after the first dose of rituximab. Patients assigned to the autologous arm will have their hematopoietic stem cells mobilized from this cytoreductive regimen. Patients with an HLA-matched sibling will undergo a non-myeloablative allogeneic HSCT. Pre-transplant conditioning will consist of fludarabine 30 mg/m^2/day and cyclophosphamide 750 mg/m^2/day x 3 days with rituximab 375 mg/m^2/day on Days -13 and -6 pre-HSCT and on Days +1 and +8 post-HSCT. The immunosuppressive regimen will consist of tacrolimus and methotrexate (MTX) to control graft-versus-host and host-versus-graft reactions. Patients without an HLA-matched sibling who have collected an adequate autologous hematopoietic cell graft, defined as at least 2.0 * 10^6 CD34+ cells/kg, will receive a preparative regimen of total body irradiation (TBI) 1200 cGy or Carmustine (BCNU) 15 mg/kg. In addition, VP-16 60 mg/kg and cyclophosphamide 100 mg/kg will be given for both autologous preparative regimens. Post-autologous HSCT therapy with rituximab 375 mg/m^2 weekly x 4 doses will commence between Days 42-75 post-HSCT.

Conditions

Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Follicular Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Autologous Transplant

Cyclophosphamide and Rituximab with Filgrastim conditioning and chemotherapy or radiation therapy prior to autologous Hematopoietic Stem Cell Transplant (HSCT). Rituximab maintenance therapy following HSCT.

Group Type: ACTIVE_COMPARATOR

Cyclophosphamide and Rituximab

Intervention Type: DRUG

Prior to undergoing HSCT, all patients will receive Cyclophosphamide 4 gm/m2 with Rituximab 375 mg/m2 x 2 doses and G-CSF support.

Filgrastim

Intervention Type: DRUG

Autologous HSCT patients will receive 10 mcg/kg/day and allogeneic HSCT patients will receive 5 mcg/kg/day subcutaneous (SQ) or intravenous (IV) starting 2 days after the initiation of Cyclophosphamide.

Chemotherapy or Radiation therapy

Intervention Type: RADIATION

Chemotherapy - BCNU 15 mg/kg IV x 1 dose to be administered over 2 hours on Day -6 pre-HSCT. VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4.

Radiation - administered at a rate of < 20 cGy/min in one of the following doses; 120 cGy/fraction are administered at no less than 4-hour intervals three times/day or 2 times/day for a total of 10 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5), or doses of 150 cGy/fraction twice daily for a total of 8 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5). VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4 pre-HSCT.

Cyclophosphamide 100 mg/kg IV x 1 dose to be administered over 2 hours on Day -2 pre-HSCT. G-CSF 5 mcg/kg SQ or IV to start on Day +5 post-HSCT and continue until ANC > 500/mm3 x 3 days.

Autologous transplant

Intervention Type: PROCEDURE

Infusion of G-CSF mobilized autologous hematopoietic stem cells

Rituximab maintenance therapy

Intervention Type: DRUG

Patients must have sufficiently recovered from autologous HSCT in order to receive rituximab maintenance therapy as specified below:

Dose #1: Day +42 post-autologous HSCT Dose #2: Day +49 post-autologous HSCT Dose #3: Day +56 post-autologous HSCT Dose #4: Day +63 post-autologous HSCT

Allogeneic Transplant

Non-myeloablative conditioning regimen followed by allogeneic Hematopoietic Stem Cell Transplant (HSCT). Graft-versus-Host Disease (GVHD) Prophylaxis therapy following HSCT.

Group Type: ACTIVE_COMPARATOR

Cyclophosphamide and Rituximab

Intervention Type: DRUG

Prior to undergoing HSCT, all patients will receive Cyclophosphamide 4 gm/m2 with Rituximab 375 mg/m2 x 2 doses and G-CSF support.

Filgrastim

Intervention Type: DRUG

Autologous HSCT patients will receive 10 mcg/kg/day and allogeneic HSCT patients will receive 5 mcg/kg/day subcutaneous (SQ) or intravenous (IV) starting 2 days after the initiation of Cyclophosphamide.

Non-myeloablative Conditioning regimen

Intervention Type: DRUG

Fludarabine 30 mg/m2 IV x 3 doses total to be administered daily over 30 minutes on Days -6, -5 and -4 pre-HSCT. Cyclophosphamide 750 mg/m IV x 3 doses total to be administered daily over 1 hour on Days -6, -5 and -4 pre-HSCT. Administer cyclophosphamide approximately 4 hours after start of fludarabine infusion. Rituximab 375 mg/m2 IV x 4 doses total to be administered on Days -13 and -6 pre HSCT and Days +1 and +8 post HSCT.

Allogeneic transplant

Intervention Type: PROCEDURE

Infusion of G-CSF mobilized allogeneic hematopoietic stem cells

GVHD Prophylaxis

Intervention Type: DRUG

Tacrolimus 0.09 mg/kg/day PO, based on body weight formulas will start on Day -2 and continue until Day +90 post-HSCT. Tacrolimus (or cyclosporine, if applicable) will be given orally in a twice-daily divided dose. Methotrexate 5 mg/m2 Intravenous Pyelogram (IVP) will be administered on Days +1, +3 and +6 post-HSCT.

Interventions

Cyclophosphamide and Rituximab

Prior to undergoing HSCT, all patients will receive Cyclophosphamide 4 gm/m2 with Rituximab 375 mg/m2 x 2 doses and G-CSF support.

Intervention Type: DRUG

Filgrastim

Autologous HSCT patients will receive 10 mcg/kg/day and allogeneic HSCT patients will receive 5 mcg/kg/day subcutaneous (SQ) or intravenous (IV) starting 2 days after the initiation of Cyclophosphamide.

Intervention Type: DRUG

Chemotherapy or Radiation therapy

Chemotherapy - BCNU 15 mg/kg IV x 1 dose to be administered over 2 hours on Day -6 pre-HSCT. VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4.

Radiation - administered at a rate of < 20 cGy/min in one of the following doses; 120 cGy/fraction are administered at no less than 4-hour intervals three times/day or 2 times/day for a total of 10 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5), or doses of 150 cGy/fraction twice daily for a total of 8 doses (1200 cGy) over 4 days (Day -8, -7, -6 and -5). VP-16 60 mg/kg IV x 1 dose to be administered over 4 hours on Day -4 pre-HSCT.

Cyclophosphamide 100 mg/kg IV x 1 dose to be administered over 2 hours on Day -2 pre-HSCT. G-CSF 5 mcg/kg SQ or IV to start on Day +5 post-HSCT and continue until ANC > 500/mm3 x 3 days.

Intervention Type: RADIATION

Non-myeloablative Conditioning regimen

Fludarabine 30 mg/m2 IV x 3 doses total to be administered daily over 30 minutes on Days -6, -5 and -4 pre-HSCT. Cyclophosphamide 750 mg/m IV x 3 doses total to be administered daily over 1 hour on Days -6, -5 and -4 pre-HSCT. Administer cyclophosphamide approximately 4 hours after start of fludarabine infusion. Rituximab 375 mg/m2 IV x 4 doses total to be administered on Days -13 and -6 pre HSCT and Days +1 and +8 post HSCT.

Intervention Type: DRUG

Allogeneic transplant

Infusion of G-CSF mobilized allogeneic hematopoietic stem cells

Intervention Type: PROCEDURE

Autologous transplant

Infusion of G-CSF mobilized autologous hematopoietic stem cells

Intervention Type: PROCEDURE

Rituximab maintenance therapy

Patients must have sufficiently recovered from autologous HSCT in order to receive rituximab maintenance therapy as specified below:

Dose #1: Day +42 post-autologous HSCT Dose #2: Day +49 post-autologous HSCT Dose #3: Day +56 post-autologous HSCT Dose #4: Day +63 post-autologous HSCT

Intervention Type: DRUG

GVHD Prophylaxis

Tacrolimus 0.09 mg/kg/day PO, based on body weight formulas will start on Day -2 and continue until Day +90 post-HSCT. Tacrolimus (or cyclosporine, if applicable) will be given orally in a twice-daily divided dose. Methotrexate 5 mg/m2 Intravenous Pyelogram (IVP) will be administered on Days +1, +3 and +6 post-HSCT.

Intervention Type: DRUG

Other Intervention Names

Cytoxan® and Rituxan; G-CSF; Etoposide and Carmustine; BCNU and VP-16; Fludarabine, Cyclophosphamide, and Rituximab; Fludara, Cytoxan®, and Rituxan; HSCT; HSCT; Rituxan; Tacrolimus and Methotrexate; Prograf® and MTX

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed recurrent Revised European American Lymphoma (REAL) classification follicle center lymphoma, follicular grades I and II, OR histologically confirmed World Health Organization (WHO) classification follicular lymphoma grades 1, 2, 3a or 3b; for either classification, the diffuse component or presence of large cleaved cells (if present) cannot be more than 50% of high power field; patients do not have to express t(14;18) to be eligible
• Received three or fewer prior regimens of chemotherapy; monoclonal antibody therapy and involved field radiation therapy will not be counted as a prior therapy
• Beyond first Complete Remission (CR) or first Partial Remission (PR) AND demonstrate chemosensitive disease; chemosensitive disease will be defined as less than 20% bone marrow involvement in the aspirate or core biopsy with follicular lymphoma AND lymph node size in axial diameter of less than 3 cm or a greater than 50% reduction in estimated lymph node volume to be measured as product of bi-dimensional measurements; Positron Emission Tomography (PET) scanning will not be used for staging or response purposes

• Patients with adequate organ function as measured by:

1. Cardiac: left ventricular ejection fraction at rest at least 45%

2. Hepatic: bilirubin less than 2 times the upper limit of normal and alanine transaminase (ALT) and aspartate aminotransferase (AST) less than 3 times the upper limit of normal

3. Renal: creatinine clearance greater than 40 mL/min

4. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), Forced expiratory volume in one second (FEV1), and Forced vital capacity (FVC) greater than 50% of predicted (corrected for hemoglobin)

• If the patient is younger than 18 years of age and they have reached the age of assent, then they must have completed the local Institutional Review Board (IRB) assent process.
• Able to receive cyclophosphamide and rituximab mobilization chemotherapy no earlier than 3 weeks from the beginning of the most recent cycle of salvage chemotherapy and no later than 6 weeks from enrollment

• Collection of an autologous or allogeneic graft of at least 2.0 * 10^6 CD34+ cells/kg
• Blood count recovery defined as Absolute Neutrophil Count (ANC) greater than 1000/mm3 and platelets greater than 100 * 10^9/L

• Off intravenous antibiotics and off amphotericin B formulations for proven, probable or possible fungal infections
• No active Cytomegalovirus (CMV) infections or for patients with CMV infection post-autograft, treated with ganciclovir, valganciclovir, or foscarnet per institutional guidelines and CMV antigenemia negative
• Mucositis resolved and off hyperalimentation

Exclusion Criteria

• Karnofsky performance score less than 70%
• Follicular lymphoma that show histologic evidence of transformation
• Uncontrolled hypertension
• Patients with uncontrolled bacterial, viral or fungal infection (currently taking medication and progression without clinical improvement).
• Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent more than 5 years previously will be reviewed on a case-by-case basis by a Protocol Chair or Medical Monitor.
• Pregnant (positive Beta Human chorionic gonadotropin (β-HCG)) or breastfeeding
• Seropositive for Human immunodeficiency virus (HIV)
• Unwilling to use contraceptive techniques during treatment
• Prior autologous or allogeneic HSCT
• Known anaphylactic reaction to rituximab

• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

City of Hope National Medical Center

Duarte, California, United States

Scripps Clinic

La Jolla, California, United States

UCSD Medical Center

La Jolla, California, United States

Stanford Hospital and Clinics

Stanford, California, United States

University of Florida College of Medicine (Shands)

Gainesville, Florida, United States

H. Lee Moffitt Cancer Center

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

BMT Group of Georgia

Atlanta, Georgia, United States

Loyola University

Atlanta, Georgia, United States

Indiana BMT at Beech Grove

Beech Grove, Indiana, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

Karmanos Cancer Institute/BMT

Detroit, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Kansas City Cancer Centers

Kansas City, Missouri, United States

Washington University/Barnes Jewish Hospital

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Duke University Medical Center

Durham, North Carolina, United States

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States

Providence Portland Medical Center

Portland, Oregon, United States

Oregon Health Sciences University

Portland, Oregon, United States

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

Baylor University Medical Center

Dallas, Texas, United States

University of Texas/MD Anderson CRC

Houston, Texas, United States

Virginia Commonwealth University MCV Hospitals

Richmond, Virginia, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA, Horowitz MM, Vose JM, Negrin RS, Laport GG. Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biol Blood Marrow Transplant. 2011 Jul;17(7):1051-7. doi: 10.1016/j.bbmt.2010.11.004. Epub 2010 Nov 10.

Reference Type: RESULT

PMID: 21073974 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

U01HL069294

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMT CTN 0202

Identifier Type: OTHER

Identifier Source: secondary_id

5U24CA076518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMTCTN0202

Identifier Type: -

Identifier Source: org_study_id