Trial Information

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

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.