Immunotherapy Using Cyclosporine, Interferon Gamma, and Interleukin-2 After High-Dose Myeloablative Chemotherapy With Autologous Stem Cell Transplantation in Treating Patients With Refractory or Relapsed Hodgkin's Lymphoma

Condition(s) targeted: Lymphoma

Intervention: aldesleukin (Drug); carmustine (Drug); cyclosporine (Drug); cytarabine (Drug); etoposide (Drug); filgrastim (Drug); melphalan (Drug); recombinant interferon gamma (Drug); autologous bone marrow transplantation (Procedure); bone marrow ablation with stem cell support (Procedure); peripheral blood stem cell transplantation (Procedure)

Phase: Phase 2/Phase 3

Status: Active, not recruiting

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Allen R. Chen, MD, PhD, MHS, Study Chair, Affiliation: Sidney Kimmel Comprehensive Cancer Center
Sharon L. Gardner, MD, Affiliation: New York University School of Medicine

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Giving immunotherapy using cyclosporine, interferon gamma, and interleukin-2 after stem cell transplantation may help the transplanted cells make an immune response and kill any remaining cancer cells. It is not yet known whether high-dose chemotherapy followed by autologous stem cell transplantation is more effective with or without immunotherapy.

PURPOSE: This randomized phase II/III trial is studying how well high-dose chemotherapy followed by autologous stem cell transplantation, cyclosporine, interferon gamma, and interleukin-2 works and compares it to high-dose chemotherapy followed by autologous stem cell transplantation only in treating patients with refractory or relapsed Hodgkin's lymphoma.

Official title: A Phase II/III Study of Immunomodulation After High Dose Myeloablative Therapy With Autologous Stem Cell Rescue for Refractory/Relapsed Hodgkin Disease

Study design: Treatment, Randomized, Active Control

Primary outcome:

Event-free survival at 3 years after stem cell rescue

Overall survival at 3 years after stem cell rescue

Secondary outcome:

Non-relapse mortality at 100 days after stem cell rescue

Graft-vs-host disease at 100 days after stem cell rescue

T-lymphocyte activity at 100 days after stem cell rescue

Invariant peptide expression at 100 days after stem cell rescue

Detailed description: OBJECTIVES:

Primary

- Phase II

- Determine the feasibility and toxicity of immunotherapy comprising cyclosporine,

interferon gamma, and interleukin-2 after high-dose myeloablative chemotherapy with autologous stem cell transplantation (ASCT) in patients with refractory or relapsed Hodgkin's lymphoma.

- Phase III

- Compare the event-free and overall survival of patients treated with vs without

this immunotherapy regimen.

Secondary

- Determine the event-free and overall survival rates, toxic effects, and response rates

to reinduction chemotherapy followed by hyperfractionated involved-field radiotherapy, high-dose chemotherapy comprising carmustine, etoposide, cytarabine, and melphalan, and ASCT in these patients.

- Correlate tumor biologic characteristics with response in patients treated with these

regimens.

- Determine the effectiveness of this immunotherapy regimen in producing autologous

graft-vs-host disease (GVHD) and auto-reactive cytotoxic T-lymphocyte activity in these patients.

- Correlate greater levels of autologous GVHD and in vitro cytolytic activity with

improved event-free and overall survival in patients treated with these regimens.

- Determine whether treatment with immunotherapy can overcome the negative prognostic

significance of p53 mutation and high serum levels of interleukin-10 and interleukin-2 receptor in these patients.

- Determine the genotoxicity of retrieval therapy and the incidence of hypermutability by

longitudinal genotoxic biomonitoring in these patients.

- Correlate HLA class II invariant peptide (CLIP) expression in tumor cells with improved

event-free and overall survival in patients treated with immunotherapy regimen.

OUTLINE: This is a nonrandomized, multicenter phase II study followed by a randomized, multicenter phase III study. Patients are stratified according to study phase (II vs III).

Patients receive 2 courses of salvage induction therapy on COG-AHOD00P1 or equivalent. Within 2-5 weeks after completion of salvage induction therapy, patients receive protocol therapy.

- Phase II: All patients receive the following treatment:

- Hyperfractionated involved-field radiotherapy: Patients who have completed prior

salvage induction therapy and have not received full tissue tolerance from prior radiotherapy may receive hyperfractionated involved-field radiotherapy twice daily for 7 days.

- High-dose preparative regimen: Beginning within 7 days after radiotherapy, patients

receive carmustine IV over 3 hours on day - 6; etoposide IV over 1 hour and

cytarabine IV over 1 hour on days - 5 to -2; and melphalan IV over 30 minutes on day

- 1.

- Autologous stem cell transplantation: Patients undergo autologous bone marrow or

peripheral blood stem cell transplantation on day 0. Patients then receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 1 and continuing until blood counts recover.

- Immunotherapy: Patients receive cyclosporine IV twice daily beginning on day 0 and

continuing until the completion of the course of interferon gamma and interleukin-2. When sufficiently recovered, patients also receive interferon gamma SC every other day for 10 doses. Beginning 2 days after the start of interferon gamma, patients also receive interleukin-2 SC once daily for 18 days.

- Phase III: Patients who respond to prior salvage induction therapy are randomized to 1

of 2 treatment arms. Patients who have progressive disease after 2 courses of prior salvage induction therapy are assigned to arm I.

- Arm I: Patients receive treatment as in phase II.

- Arm II: Patients receive treatment as in phase II without immunotherapy. In both

phases, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed at 1 year.

PROJECTED ACCRUAL: A total of 156 patients (25 for phase II and 131 for phase III) will be accrued for this study within 5. 4 years.

Minimum age: N/A. Maximum age: 30 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Diagnosis of Hodgkin's lymphoma

- Histologically confirmed at original diagnosis AND at relapse or disease

progression

- Relapsed or refractory to conventional therapy

- No recurrence without B symptoms or bulky disease at least 1 year after completion of

minimal systemic therapy defined by either of the following:

- Stage IA/IIA with nodal disease previously treated with radiotherapy only

- Stage IA/IIA with nodal disease previously treated with less than 3 courses of

standard dose chemotherapy

- Concurrently enrolled on the COG-AHOD00P1 salvage chemotherapy study OR received other

appropriate salvage therapy (e. g., ifosfamide and vinorelbine)

PATIENT CHARACTERISTICS:

Age

- Under 30

Performance status

- ECOG 0-2 (for adults)

- Lansky 50-100% (for children)

Life expectancy

- At least 2 months

Hematopoietic

- Absolute neutrophil count at least 500/mm^3

Hepatic

- Bilirubin no greater than 1. 5 times normal

- SGPT less than 2. 5 times normal

Renal

- Creatinine no greater than 1. 5 times normal OR

- Creatinine clearance or radioisotope glomerular filtration rate at least 70

mL/min/1. 73 m^2

Cardiovascular

- Shortening fraction at least 27% by echocardiogram OR

- Ejection fraction at least 50% by MUGA

Pulmonary

- No evidence of dyspnea at rest

- No exercise intolerance

- DLCO at least 50% (patients 8 years of age and over)

Other

- Not pregnant or nursing

- Negative pregnancy test

- No concurrent serious illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

- Recovered from prior immunotherapy

- At least 1 week since prior antineoplastic biologic agents

- More than 1 week since prior growth factors

- No prior stem cell transplantation

- No other concurrent immunomodulating agents

Chemotherapy

- See Disease Characteristics

- More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)

and recovered

- No other concurrent anticancer chemotherapy

Endocrine therapy

- No concurrent steroids, including dexamethasone as an antiemetic

Radiotherapy

- See Disease Characteristics

- Recovered from prior radiotherapy

Surgery

- Not specified

Other

- No concurrent participation in another COG therapeutic study

Comprehensive Cancer Center at University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Phoenix Children's Hospital, Phoenix, Arizona 85016-7710, United States

Arkansas Cancer Research Center at University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States

Children's Hospital and Research Center - Oakland, Oakland, California 94609-1809, United States

Children's Hospital of Orange County, Orange, California 92868, United States

Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California 90095-1781, United States

Kaiser Permanente Medical Center - Oakland, Sacramento, California 95825, United States

Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, United States

Children's National Medical Center, Washington, District of Columbia 20010-2970, United States

All Children's Hospital, St. Petersburg, Florida 33701, United States

Kaplan Cancer Center at St. Mary's Medical Center, West Palm Beach, Florida 33407, United States

Miami Children's Hospital, Miami, Florida 33155, United States

Nemours Children's Clinic, Jacksonville, Florida 32207, United States

St. Joseph's Cancer Institute at St. Joseph's Hospital, Tampa, Florida 33607, United States

University of Florida Shands Cancer Center, Gainesville, Florida 32610-0232, United States

University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 33136, United States

Emory University Hospital - Atlanta, Atlanta, Georgia 30322, United States

Children's Memorial Hospital - Chicago, Chicago, Illinois 60614, United States

Southern Illinois University School of Medicine, Springfield, Illinois 62794-9620, United States

Indiana University Cancer Center, Indianapolis, Indiana 46202-5289, United States

St. Vincent Indianapolis Hospital, Indianapolis, Indiana 46260, United States

Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center, Kansas City, Kansas 66160-7357, United States

Kosair Children's Hospital, Louisville, Kentucky 40232, United States

Children's Hospital of New Orleans, New Orleans, Louisiana 70118, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States

Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, United States

Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201-1379, United States

C.S. Mott Children's Hospital at University of Michigan, Ann Arbor, Michigan 48109-0238, United States

Hurley Medical Center, Flint, Michigan 48503, United States

Spectrum Health Cancer Care - Butterworth Campus, Grand Rapids, Michigan 49503-2560, United States

Van Elslander Cancer Center at St. John Hospital and Medical Center, Grosse Pointe Woods, Michigan 48236, United States

Children's Hospital of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

Fairview University Medical Center - University Campus, Minneapolis, Minnesota 55455, United States

Mayo Clinic Cancer Center, Rochester, Minnesota 55905, United States

University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, United States

Children's Mercy Hospital, Kansas City, Missouri 64108, United States

Hackensack University Medical Center Cancer Center, Hackensack, New Jersey 07601, United States

Long Island Cancer Center at Stony Brook University Hospital, Stony Brook, New York 11794-8174, United States

Mount Sinai Medical Center, New York, New York 10029, United States

New York Medical College, Valhalla, New York 10595, United States

Roswell Park Cancer Institute, Buffalo, New York 14263-0001, United States

SUNY Upstate Medical University Hospital, Syracuse, New York 13210, United States

Children's Medical Center - Dayton, Dayton, Ohio 45404-1815, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States

Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106-5000, United States

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850, United States

Hopital Sainte Justine, Montreal, Quebec H3T 1C5, Canada

Saskatoon Cancer Centre at the University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada

Hollings Cancer Center at Medical University of South Carolina, Charleston, South Carolina 29425, United States

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

CCOP - Scott and White Hospital, Temple, Texas 76508, United States

Cook Children's Medical Center - Fort Worth, Fort Worth, Texas 76104-9958, United States

Covenant Children's Hospital, Lubbock, Texas 79410, United States

Methodist Children's Hospital of South Texas, San Antonio, Texas 78229-3993, United States

Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas, Texas 75390, United States

Texas Tech University Health Sciences Center School of Medicine, Amarillo, Texas 79106, United States

University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, United States

Children's Hospital of the King's Daughters, Norfolk, Virginia 23507-1971, United States

Princess Margaret Hospital for Children, Perth, Western Australia 6001, Australia

Marshfield Clinic - Marshfield Center, Marshfield, Wisconsin 54449, United States

Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States

St. Vincent Hospital Regional Cancer Center, Green Bay, Wisconsin 54307-3508, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: November 2003
Last updated: May 23, 2008