Combination Chemotherapy in Treating Children With Refractory or Relapsed Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as ifosfamide and vinorelbine, work in different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating children who have refractory or relapsed Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Determine the response rate (overall and within strata) in both minimally pretreated, low-risk and heavily pretreated, high-risk children with refractory or relapsed Hodgkin's lymphoma treated with ifosfamide and vinorelbine with filgrastim (G-CSF). Determine the cardiac, hepatic, renal, and hematologic toxicity of this regimen in minimally-pretreated, low-risk patients. Determine the toxic death rate in minimally pretreated, low-risk patients treated with this regimen. Determine whether this treatment regimen can mobilize sufficient hematopoietic stem cells (CD34) for subsequent stem cell transplantation in minimally pretreated, low-risk patients. Determine the incidence of hypermutability by longitudinal genotoxic biomonitoring of patients treated with this regimen. Determine the prognostic significance of biological markers, including serum interleukin (IL)-10 receptor, serum IL-2 receptor, p53, and mdm-2 in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients are stratified by prior therapy (minimally pretreated, low-risk vs heavily pretreated, high-risk). Patients receive ifosfamide IV over 24 hours on days 1-4 and vinorelbine IV over 6-10 minutes on days 1 and 5. Patients also receive filgrastim (G-CSF) subcutaneously or IV over 15-30 minutes beginning 24-36 hours after completion of vinorelbine and continuing daily until blood counts recover. Treatment repeats at least every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients may receive a third course of therapy at the discretion of the investigator. Heavily pretreated, high-risk patients who achieve a complete response are eligible for stem cell transplantation. Patients undergo peripheral blood stem cell (PBSC) collection during hematopoietic recovery after the second course of chemotherapy. Patients with sufficient PBSCs collected may undergo PBSC transplantation on protocol COG-AHOD0121. Patients are followed at 1, 6, and 12 months and then periodically thereafter. PROJECTED ACCRUAL: A total of 66 patients will be accrued for this study within 1.5 years.

Official Title
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A Pilot Study of Re-Induction Chemotherapy With Ifosfamide, and Vinorelbine (IV) in Children With Refractory/Relapsed Hodgkin's Disease

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: ifosfamide
* Drug: vinorelbine tartrate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed refractory or relapsed Hodgkin's lymphoma Mixed cellularity, not otherwise specified (NOS) Lymphocytic depletion, NOS Lymphocytic depletion, diffuse fibrosis Lymphocytic depletion, reticular Lymphocytic predominance, NOS Lymphocytic predominance, diffuse Lymphocytic predominance, nodular Hodgkin's paragranuloma NOS Hodgkin's granuloma Hodgkin's sarcoma Nodular sclerosis, NOS Nodular sclerosis, cellular phase Nodular sclerosis, lymphocytic predominance Nodular sclerosis, mixed cellularity Nodular sclerosis, lymphocytic depletion Other (type not specified) In first relapse Metastasis to bone marrow with granulocytopenia, anemia, and/or thrombocytopenia allowed Not enrolled on POG-9426 unless there is an extranodal site of recurrence PATIENT CHARACTERISTICS: Age: Under 30 at diagnosis Performance status: Lansky 60-100% (for patients 16 years and under) Karnofsky 60-100% (for patients over 16 years) Life expectancy: At least 2 months Hematopoietic: See Disease Characteristics Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 75,000/mm^3 (transfusion independent) Hepatic: Bilirubin no greater than 1.5 times normal SGOT or SGPT less than 2.5 times normal Renal: Creatinine no greater than 1.5 times normal Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Cardiovascular: Shortening fraction at least 27% by echocardiogram OR Ejection fraction at least 50% by gated radionuclide Other: No other concurrent serious illness No known hypersensitivity to E. coli-derived proteins, filgrastim (G-CSF), or any other component of study drugs PRIOR CONCURRENT THERAPY: Biologic therapy: No concurrent immunomodulating agents Chemotherapy: At least 2 weeks since prior chemotherapy (3 weeks for nitrosoureas) and recovered No other concurrent anticancer chemotherapy Endocrine therapy: No concurrent steroids No concurrent corticosteroids (e.g., dexamethasone) Radiotherapy: Recovered from prior radiotherapy Surgery: Not specified

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ifosfamide, vinorelbine, filgrastim)<br>Patients receive ifosfamide IV over 24 hours on days 1-4 and vinorelbine tartrate IV over 6-10 minutes on days 1 and 5. Patients also receive filgrastim (G-CSF) subcutaneously or IV over 15-30 minutes beginning 24-36 hours after completion of vinorelbine and continuing daily until blood counts recover. Treatment repeats at least every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients may receive a third course of therapy at the discretion of the investigator. Heavily pretreated, high-risk patients who achieve a complete response are eligible for stem cell transplantation. Patients undergo peripheral blood stem cell (PBSC) collection during hematopoietic recovery after the second course of chemotherapy. Patients with sufficient PBSCs collected may undergo PBSC transplantation on protocol COG-AHOD0121. | Biological: filgrastim<br>* subcutaneously or IV over 15-30 minutes beginning 24-36 hours after completion of vinorelbine and continuing daily until blood counts recover.<br>Drug: ifosfamide<br>* V over 24 hours on days 1-4<br>Drug: vinorelbine tartrate<br>* IV over 6-10 minutes on days 1 and 5.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Overall response includes complete response (CR) or partial response (PR). | After 2 cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of successful PBSC harvest during re-induction defined as the ability to harvest 5 x 10^6 CD34+ cells/kg | Will be calculated. | After 2 cycles | 
| Biologic markers |  | At enrollment and during/after therapy | 
| Cardiac, hepatic, renal, hematologic toxicity |  | Within 1 month of completion of therapy | 
| Toxic death |  | Within 1 month of Completion of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent/refractory childhood Hodgkin lymphoma, childhood lymphocyte predominant Hodgkin lymphoma, childhood lymphocyte depletion Hodgkin lymphoma, childhood nodular sclerosis Hodgkin lymphoma, childhood mixed cellularity Hodgkin lymphoma