Chemotherapy With or Without Additional Chemotherapy and/or Radiation Therapy in Treating Children With Newly Diagnosed Hodgkin's Disease

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial is studying different chemotherapy regimens given with or without radiation therapy to compare how well they work in treating children with newly diagnosed Hodgkin's disease. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Giving the drugs in different combinations may kill more cancer cells. Radiation therapy uses high-energy x-rays to damage cancer cells. It is not yet known if chemotherapy is more effective with or without additional chemotherapy and/or radiation therapy in treating Hodgkin's disease.

Detailed Description
-----------------
OBJECTIVES: I. To compare response-based therapy to standard therapy for intermediate risk Hodgkin disease. II. To determine whether involved field radiation therapy (IFRT) can be eliminated based upon early and complete response to multiagent chemotherapy. III. To determine whether the addition of an additional two cycles of chemotherapy (DECA) can improve outcome in those with a slow early response to standard chemotherapy. IV. To prospectively collect information on the individual prognostic significance of the following presenting factors: erythrocyte sedimentation rate, circulating levels of IL-10, each of the B symptoms - fever, night sweats, weight loss, nodal aggregate > 6 cm, large mediastinal mass > 1/3 thoracic diameter and number of involved nodal sites, histology, albumin, blood counts, sex and age. V. To study the reliability and utility of [18F] -Fluorodeoxyglucose (FDG) Imaging (PET scans) as an imaging modality in Hodgkin disease. VI. To determine the frequency and severity of late effects of therapy including thyroid dysfunction, infertility, cardiotoxicity, pulmonary toxicity and second malignant neoplasms. VII. To serve as the therapeutic companion to biology studies in Hodgkin disease and correlate those results with response to therapy, event free-survival and overall survival. OUTLINE: This is a randomized, multicenter study. ARM I (ALL PATIENTS-OFF THERAPY BEFORE CALLBACK-INDUCTION CHEMOTHERAPY [ABVE-PC]): Patients receive doxorubicin intravenously (IV) over 10-30 minutes on days 1-2, bleomycin sulfate IV over 10-20 minutes or subcutaneously (SC) and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, oral prednisone 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. At the end of initial chemotherapy, patients undergo evaluation for response. Patients with less than 60% disease reduction are considered to have slow early response (SER). Patients with 60% or more disease reduction are considered to have rapid early response (RER). RER: Patients receive 2 additional courses of ABVE-PC chemotherapy. After completion of treatment, patients are randomized to 1 of 4 treatment arms. ARM II: Patients with sustained complete response (CR) undergo involved field radiation therapy (IFRT) approximately 3 weeks after the last day of ABVE-PC course 4 for 5 days a week. ARM III: Patients with sustained CR receive no further treatment. ARM IV: Patients with very good partial response (VGPR), partial response (PR) or stable disease (SD) undergo IFRT approximately 3 weeks after the last day of ABVE-PC course 4 for 5 days a week. ARM V: Patients with progressive disease are taken off therapy and treated their physician's discretion. SER: Patients are randomized to 1 of 2 treatment arms. ARM VI: Patients receive dexamethasone IV over 15 minutes, etoposide IV over 3 hours, cytarabine IV over 3 hours on days 1-2, and receive 2 drops of dexamethasone ophthalmic solution every 6 hours on days 1, 2 and 3. Patients also receive cisplatin PO or IV over 12 hours as pre-hydration followed by continuous IV over 6 hours on day 1 and G-CSF SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After these 2 courses, patients then receive 2 additional courses of ABVE-PC chemotherapy. ARM VII: Patients receive 2 courses of ABVE-PC chemotherapy. In both SER arms, patients with sustained CR or PR undergo IFRT approximately 3 weeks after the last course of chemotherapy. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
-----------------
A Phase III Groupwide Study of Dose-Intensive Response-Based Chemotherapy and Radiation Therapy for Children and Adolescents With Newly Diagnosed Intermediate Risk Hodgkin Disease

Conditions
-----------------
Childhood Lymphocyte-Depleted Classical Hodgkin Lymphoma, Childhood Mixed Cellularity Classical Hodgkin Lymphoma, Childhood Nodular Lymphocyte Predominant Hodgkin Lymphoma, Childhood Nodular Sclerosis Classical Hodgkin Lymphoma, Stage I Childhood Hodgkin Lymphoma, Stage II Childhood Hodgkin Lymphoma, Stage III Childhood Hodgkin Lymphoma, Stage IV Childhood Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Biological: Bleomycin Sulfate
* Drug: Cisplatin
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Biological: Filgrastim
* Radiation: Involved-Field Radiation Therapy
* Drug: Prednisone
* Drug: Vincristine Sulfate Liposome


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with newly diagnosed, pathologically confirmed Hodgkin disease (all histologies) are eligible for this protocol if they meet the following clinical stage guidelines: All Stage IB regardless of bulk disease All Stage IIB regardless of bulk disease Stage IA only with bulk disease Stage IIA only with bulk disease All Stage IAE, IIAE regardless of bulk disease All Stage IIIA, IIIAE, IIIAS, IIIAE+S regardless of bulk disease All Stage IVA, IVAE regardless of bulk disease May not be staged by laparotomy alone Surgically staged patients must also have presurgical staging Bilirubin no greater than 1.5 times normal SGOT or SGPT less than 2.5 times normal Creatinine no greater than 1.5 times normal Creatinine clearance greater than 40 mL/min Radioisotope glomerular filtration rate greater than 70 mL/min Shortening fraction at least 27% by echocardiogram Ejection fraction at least 50% by MUGA No pathologic prolongation of QTc interval on 12-lead electrocardiogram FEV_1/FVC greater than 60% by pulmonary function test Pulse oximetry greater than 94% No evidence of dyspnea at rest No exercise intolerance Adequate venous access Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior chemotherapy At least 1 month since prior corticosteroids except prednisone for respiratory distress No prior radiotherapy

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Patients off-therapy before callback-Induction only)<br>Patients receive doxorubicin IV over 10-30 minutes on days 1-2, bleomycin sulfate IV over 10-20 minutes or SC and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, oral prednisone 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|
| Experimental: Arm II (RER with CR [ABVE-PC, IFRT])<br>Patients receive doxorubicin IV over 10-30 minutes on days 1-2, bleomycin IV over 10-20 minutes or SC and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, prednisone PO 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. Patients receive an additional 2 courses of ABVE-PC. Patients with sustained CR undergo IFRT approximately 3 weeks after the last day of ABVE course 4. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Radiation: Involved-Field Radiation Therapy<br>* Undergo IFRT<br>* Other names: Involved field radiotherapy;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|
| Experimental: Arm III (RER with CR [ABVE-PC])<br>Patients receive doxorubicin IV over 10-30 minutes on days 1-2, bleomycin IV over 10-20 minutes or SC and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, prednisone PO 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. Patients receive an additional 2 courses of ABVE-PC. Patients with sustained CR are randomized to receive no further treatment. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|
| Experimental: Arm IV (RER with less than CR [ABVE-PC, IFRT])<br>Patients receive doxorubicin IV over 10-30 minutes on days 1-2, bleomycin IV over 10-20 minutes or SC and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, prednisone PO 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. Patients receive an additional 2 courses of ABVE-PC. Patients with VGPR, PR or SD undergo IFRT approximately 3 weeks after the last day of ABVE-PC course 4 for 5 days a week. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Radiation: Involved-Field Radiation Therapy<br>* Undergo IFRT<br>* Other names: Involved field radiotherapy;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|
| Experimental: Arm V (RER with PD)<br>Patients receive doxorubicin IV over 10-30 minutes on days 1-2, bleomycin IV over 10-20 minutes or SC and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, prednisone PO 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. Patients with PD are taken off therapy. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|
| Experimental: Arm VI (SER [DECA, ABVE-PC, IFRT])<br>Patients receive dexamethasone IV over 15 minutes, etoposide IV over 3 hours, and cytarabine IV over 3 hours on days 1-2. Patients receive 2 drops of dexamethasone ophthalmic solution every 6 hours on days 1, 2 and 3. Patients also receive cisplatin PO or IV over 12 hours as pre-hydration followed by continuous IV over 6 hours on day 1 and G-CSF SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients then receive 2 additional courses of ABVE-PC chemotherapy. Patients with sustained complete or partial response undergo IFRT approximately 3 weeks after the last course of chemotherapy. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV<br>* Other names: Visumetazone;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Radiation: Involved-Field Radiation Therapy<br>* Undergo IFRT<br>* Other names: Involved field radiotherapy;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|
| Experimental: Arm VII (SER [ABVE-PC, IFRT])<br>Patients receive doxorubicin IV over 10-30 minutes on days 1-2, bleomycin IV over 10-20 minutes or SC and vincristine IV on days 1 and 8, etoposide IV over 1 hour on days 1-3, prednisone PO 2 or 3 times daily on days 1-7, and cyclophosphamide IV over 1 hour on day 1. Patients receive filgrastim (G-CSF) SC beginning on day 2 and continuing until blood counts recover (G-CSF is held on day 8). Treatment repeats every 21 days for 2 courses in the absence of progressive disease. Patients receive 2 additional courses of ABVE-PC. Patients with sustained complete or partial response undergo IFRT approximately 3 weeks after the last course of chemotherapy. | Biological: Bleomycin Sulfate<br>* Given IV or SC<br>* Other names: Oil Bleo;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Radiation: Involved-Field Radiation Therapy<br>* Undergo IFRT<br>* Other names: Involved field radiotherapy;Drug: Prednisone<br>* Given orally<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Probability of event-Free survival which is defined as the time from study entry to treatment failure (disease progression, disease recurrence, biopsy positive residual after completion of all protocol therapy), occurrence of a second malignant neoplasm, or death from any cause. Patients without report of such events where censored at last contact. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response Assessed by Modified RECIST Criteria | Number of participants with complete response and very good partial response at the end of protocol therapy. | Protocol therapy: the overall duration of which is: (n=1527) an average of 137.1 days, median 133.0 days, interquartile range: 101.0, 164.0 days. | 
| Grade 3 or 4 Non-hematologic Toxicity | Occurrence of any grade 4 non-hematologic toxicity or grade 3 non-hematologic toxicity which doesn't respond to treatment within 7 days despite recommended therapy modification, or toxic death, which is any death primarily attributable to treatment. Grade 3 is defined to be severe or medically significant but not immediate life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 refers to toxicities with life-threatening consequences; urgent intervention indicated. | Protocol therapy: the overall duration of which is: (n=1684) an average of 137.3 days, median 133.0 days, interquartile range: 101.0, 164.0 days. | 
| Overall Survival | Probability of overall survival which is defined as the time from study entry to death from any cause. Patients alive where censored at last contact. | 5 years |