Clinical trial NCT00070187: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Lymphoma
Keywords: recurrent adult Hodgkin lymphoma
recurrent/refractory childhood Hodgkin lymphoma
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-10-07
Enrollment: 24
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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.

Eligibility 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

Primary outcomes:
measure: Incidence of death, excluding death due to disease, during the period of time from day 0 (transplant) through day 100 post transplant
timeFrame: Day 0 (transplant) through Day 100 (Post transplant)
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Comprehensive Cancer Center at University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
state: Arkansas
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center at UCLA
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center - Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente Medical Center - Oakland
state: California
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: St. Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Cancer Institute at St. Joseph's Hospital
state: Florida
city: West Palm Beach
country: United States
facility: Kaplan Cancer Center at St. Mary's Medical Center
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital - Atlanta
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Indianapolis Hospital
state: Indiana
city: Kansas City
country: United States
facility: Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Children's Hospital of New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital at University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Cancer Care - Butterworth Campus
state: Michigan
city: Grosse Pointe Woods
country: United States
facility: Van Elslander Cancer Center at St. John Hospital and Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: Fairview University Medical Center - University Campus
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center Cancer Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Stony Brook
country: United States
facility: Long Island Cancer Center at Stony Brook University Hospital
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Children's Medical Center - Dayton
state: Ohio
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Amarillo
country: United States
facility: Texas Tech University Health Sciences Center School of Medicine
state: Texas
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Lubbock
country: United States
facility: Covenant Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Norfolk
country: United States
facility: Children's Hospital of the King's Daughters
state: Virginia
city: Green Bay
country: United States
facility: St. Vincent Hospital Regional Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic - Marshfield Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre at the University of Saskatchewan
state: Saskatchewan
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Allen R. Chen, MD, PhD, MHS
role: STUDY_CHAIR
affiliation: NYU Langone Health
name: Sharon L. Gardner, MD
role: STUDY_CHAIR
References:
citation: 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 BEAM: a COG study. [Abstract] Blood 110 (11): A-1896, 2007.