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

Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00070187
• Other study ID #: AHOD0121
• Secondary ID: CDR0000330135COG
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: October 3, 2003
• Last updated: October 16, 2013
• Start date: November 2003

Study information

• Verified date: October 2013
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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 II part of the study was completed and should have proceeded to Phase III; however long delay occurred due to some proposed protocol changes to Phase III , so long that the study got permanently closed ***********

• 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. primary completion date: June 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 30 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hodgkin Disease
• Lymphoma

Intervention

Biological:
• aldesleukin
Given IV
• filgrastim
Given IV
• recombinant interferon gamma
Given IV

Drug:
• carmustine
Given IV
• cyclosporine
Given IV
• cytarabine
Given IV
• etoposide
Given IV
• melphalan
Given IV

Procedure:
• autologous bone marrow transplantation

• bone marrow ablation with stem cell support

• peripheral blood stem cell transplantation

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan
United States	Texas Tech University Health Sciences Center School of Medicine	Amarillo	Texas
United States	C.S. Mott Children's Hospital at University of Michigan	Ann Arbor	Michigan
United States	Emory University Hospital - Atlanta	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Comprehensive Cancer Center at University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Children's Medical Center - Dayton	Dayton	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Spectrum Health Cancer Care - Butterworth Campus	Grand Rapids	Michigan
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	St. Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Jonsson Comprehensive Cancer Center at UCLA	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Miami Children's Hospital	Miami	Florida
United States	University of Miami Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Children's Hospital of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Fairview University Medical Center - University Campus	Minneapolis	Minnesota
United States	Children's Hospital of New Orleans	New Orleans	Louisiana
United States	Mount Sinai Medical Center	New York	New York
United States	Children's Hospital of the King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center - Oakland	Oakland	California
United States	Children's Hospital of Orange County	Orange	California
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Kaiser Permanente Medical Center - Oakland	Sacramento	California
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	All Children's Hospital	St. Petersburg	Florida
United States	Long Island Cancer Center at Stony Brook University Hospital	Stony Brook	New York
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	CCOP - Scott and White Hospital	Temple	Texas
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

References & Publications (1)

Chen AR, Hutchison R, Hess A, et al.: Clinical outcomes of patients with recurrent/refractory Hodgkin disease receiving cyclosporine, interferon-, and interleukin-2 immunotherapy to induce auto-reactivity after autologous stem cell transplantation with BE

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of death, excluding death due to disease, during the period of time from day 0 (transplant) through day 100 post transplant	Death, excluding death due to disease, during the period of time from Day 0 (transplant) through Day 100 post transplant.	Day 0 (transplant) through Day 100 (Post transplant)	Yes