Trial Information

First International Inter-Group Study for Classical Hodgkin's Lymphoma in Children and Adolescents

OBJECTIVES:

Primary

- Determine whether the 5-year event-free survival (EFS) rate in pediatric patients with
Hodgkin's lymphoma with an adequate response after 2 courses of vincristine, etoposide,
prednisone, and doxorubicin hydrochloride (OEPA) (without radiotherapy) are consistent
with an estimated target EFS rate of 90%.

- Compare the EFS (without a deterioration) of patients treated with procarbazine
hydrochloride vs dacarbazine (treatment groups 2 and 3).

- Determine the treatment outcome of a standardized risk-adapted relapse strategy in
these patients.

Secondary

- Determine whether the 5-year EFS rate in patients with Hodgkin's lymphoma with an
inadequate response after 2 OEPA courses and standard involved-field radiotherapy are
consistent with an estimated target EFS rate of 90%.

- Determine whether a positive positron emission tomography scan before planned high-dose
chemotherapy with autologous stem cell transplantation has a negative prognostic
significance.

- Compare the effect of dacarbazine vs procarbazine on the rate of infertility in males
and premature menopause in females (treatment groups 2 and 3).

Tertiary

- Determine the impact of real-time central staging and response assessment on treatment
outcome in these patients.

OUTLINE: This is a randomized, controlled, parallel-group, open-label, multicenter study.
Patients are stratified according to staging and response assessment (central vs local) and
disease stage (IA/B or IIA [first-line treatment group 1] vs I_EA/B, II_EA, IIB, or IIIA
[first-line treatment group 2] vs II_EB, III_E A/B, IIIB, or IVA/B [first-line treatment
group 3]).

- First-line treatment group 1: Patients receive oral prednisone (or prednisolone) 3
times daily on days 1-15, vincristine IV on days 1, 8, and 15, doxorubicin
hydrochloride IV over 1-6 hours on days 1 and 15, and etoposide (or etoposide
phosphate) IV over 1-2 hours on days 1-5 (OEPA).

Treatment repeats every 28 days for 2 courses in the absence of unacceptable toxicity.
Patients are assessed by fludeoxyglucose F 18 positron emission tomography (^18FDG-PET)
scan. Patients with inadequate response undergo radiotherapy within 35 days after completion
of OEPA.

- First-line treatment group 2: Patients receive OEPA as in group 1. After completion of
OEPA, patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral prednisone (or prednisolone) 3 times daily and oral
procarbazine hydrochloride 2-3 times a day on days 1-15 and vincristine IV and
cyclophosphamide IV over 1 hour on days 1 and 8 (COPP).

- Arm II: Patients receive oral prednisone (or prednisolone) 3 times daily on days
1-15, dacarbazine IV over 15-30 minutes on days 1-3, and vincristine IV and
cyclophosphamide IV over 1 hour on days 1 and 8 (COPDAC).

In both arms, treatment repeats every 28 days for 2 courses in the absence of unacceptable
toxicity. Patients are assessed by ^18FDG-PET scan. Patients with an inadequate response
undergo radiotherapy within 35 days after completion of COPP or COPDAC.

- First-line treatment group 3: Patients receive OEPA as in group 1. After completion of
OEPA, patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive COPP as in arm I of group 2.

- Arm II: Patients receive COPDAC as in arm II of group 2. In both arms, treatment
repeats every 28 days for 4 courses in the absence of unacceptable toxicity.
Patients are assessed by ^18FDG-PET scan. Patients with an inadequate response
undergo radiotherapy within 35 days after completion of COPP or COPDAC.

Patients with biopsy-confirmed disease progression OR relapse after first-line treatment on
this study or on protocols DAL-HD 90, GPOH-HD 95, GPOHHD 2002 Pilot, or similar treatment
proceed to second-line therapy. Patients are stratified according to relapse/progression
status (late relapse from first-line treatment group 1 [second-line treatment group 1] vs
early relapse from first-line treatment groups 1, 2, or 3 or late relapse from first-line
treatment groups 2 or 3 [second-line treatment group 2] vs disease progression [second-line
treatment group 3]). Patients undergo a ^18FDG-PET scan prior to beginning second-line
therapy.

- Second-line treatment group 1: Patients receive ifosfamide IV over 22 hours and
etoposide IV over 1-2 hours and oral prednisone three times daily on days 1-5 (IEP).
Patients then receive doxorubicin hydrochloride IV over 1-6 hours, bleomycin IV,
vinblastine IV, and dacarbazine IV over 15-30 minutes on days 22 and 36 (ABVD).
Treatment repeats every 50 days for 2 courses in the absence of disease progression or
unacceptable toxicity.

After chemotherapy treatment, patients undergo radiotherapy.

- Second-line treatment group 2: Patients receive IEP and ABVD as in group 1. Autologous
stem cells are collected after course 1 or 2 of IEP/ABVD.

After chemotherapy, patients with an adequate response undergo radiotherapy. Patients with
an inadequate response undergo high-dose chemotherapy comprising carmustine IV over 1-2
hours on day -7, etoposide IV and cytarabine IV over 30 minutes twice daily on days -6 to
-3, and melphalan IV over 1½ hours on day -2. Patients then undergo autologous hematopoietic
stem cell transplantation (HSCT).

Patients undergo a ^18FDG-PET scan on day 50-54. Patients with ^18FDG-PET scan positive
disease undergo radiotherapy.

- Second-line treatment group 3: Patients receive IEP and ABVD as in group 1. All
patients then undergo high-dose chemotherapy and HSCT as in group 2.

Patients undergo a ^18FDG-PET scan on day 50-54. Patients with ^18FDG-PET scan positive
disease undergo radiotherapy.

After completion of study therapy, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 2,150 patients will be accrued for this study.