Comparison of Two Combination Chemotherapy Regimens With Either Vincristine or Vinblastine in Treating Patients With Advanced Anaplastic Large Cell Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known if combination chemotherapy with vinblastine is more effective than combination chemotherapy with vincristine in treating advanced anaplastic large cell lymphoma. PURPOSE: Randomized phase III trial to compare the effectiveness of two combination chemotherapy regimens with either vinblastine or vincristine in treating patients who have newly diagnosed advanced anaplastic large cell lymphoma.

Detailed Description
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OBJECTIVES: Compare the efficacy of a consolidation chemotherapy regimen comprising doxorubicin and prednisone in combination with vincristine vs vinblastine, in terms of event-free survival, in patients with advanced anaplastic large cell lymphoma. Compare overall survival of patients treated with these regimens. Compare the toxic effects of these regimens in these patients. Correlate biological tumor characteristics and outcome in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are randomized at enrollment to receive either Standard APO regimen or a consolidation regimen including vinblastine (VBL). Induction therapy: All Patients receive doxorubicin IV over 15 minutes on days 1 and 22; vincristine IV on days 1, 8, 15, 22, and 29; oral prednisone 3 times daily on days 1-28; and intrathecal (IT) methotrexate on days 1, 8, and 22 (patients with central nervous system (CNS) disease at diagnosis receive additional methotrexate IT on days 15, 29, and 36). Patients undergo restaging after Induction such that consolidation therapy is started on day 43. All patients with complete response (CR), complete response unconfirmed (CRu) or partial response (PR) proceed to Consolidation based on CT or MRI scans at the end of induction (week 6). All other patients will be removed from protocol therapy and will be followed until they meet the criteria for off study. Follow-up data will be required unless consent is withdrawn. Standard APO (Arm I): Patients receive course-specific regimens without vinblastine. Courses 1-3: Patients receive doxorubicin IV over 15 minutes, vincristine IV, and methotrexate IT on day 1 and oral prednisone three times daily and oral mercaptopurine once daily on days 1-5. Courses 4-5: Patients receive doxorubicin, vincristine, prednisone, and mercaptopurine as in courses 1-3. Courses 6-15: Patients receive vincristine, prednisone, and mercaptopurine as in courses 1-3 and methotrexate IV on day 1. Consolidation with vinblastine (Arm II): Patients receive course-specific regimens including vinblastine. Courses 1-3: Patients receive doxorubicin, methotrexate IT, prednisone, and mercaptopurine as in arm I and vinblastine IV over 1 minute on days 1, 8, and 15. Courses 4-5: Patients receive doxorubicin, prednisone, and mercaptopurine as in arm I and vinblastine as in arm II (courses 1-3). Courses 6-15: Patients receive prednisone and mercaptopurine as in arm I, vinblastine as in arm II (courses 1-3), and methotrexate IV on day 1. In both arms and all courses, treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity. Patients are followed monthly for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 200-250 patients (100-125 per treatment arm) will be accrued for this study within 5 years.

Official Title
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A Phase III Trial of Treatment of Advanced-Stage Anaplastic Large Cell Lymphoma (ALCL) With Standard APO (Doxorubicin, Prednisone, Vincristine) Versus Consolidation With a Regimen Including Vinblastine

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: prednisone
* Drug: vinblastine sulfate
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Newly diagnosed advanced anaplastic large cell lymphoma Cluster of differentiation antigen 30 (CD30+) Murphy stage III or IV No B-cell large cell lymphoma No disease limited to the skin (regardless of how wide-spread) PATIENT CHARACTERISTICS: Age Under 21 Performance status Not specified Life expectancy Not specified Hematopoietic Not specified Hepatic Bilirubin no greater than 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) or alanine transaminase (ALT) less than 2.5 times ULN (unless due to lymphoma) Renal Not specified Cardiovascular Shortening fraction (SF) at least 27% by echocardiogram OR Ejection fraction (EF) at least 50% by radionuclide angiogram Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Prior steroids for management of a mediastinal mass allowed Radiotherapy Prior limited-dose radiotherapy for a mediastinal mass allowed Surgery Not specified

Ages Eligible for Study
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Maximum Age: 20 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard APO with Vincristine (Arm I )<br>In courses 1-3, patients receive doxorubicin hydrochloride (30 mg/m2) IV over 15 minutes, vincristine sulfate (1.5 mg/m2 (maximum dose 2 mg)) IV, and methotrexate intrathecally (age-adjusted dosing) (IT) on day 1 and oral prednisone (40 mg/m2/day) three times daily and oral mercaptopurine (225 mg/m2) once daily on days 1-5. In courses 4 and 5, patients receive doxorubicin (30 mg/m2), vincristine sulfate (1.5 mg/m2 (Maximum dose 2 mg)), prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in courses 1-3. In courses 6-15, patients receive vincristine sulfate (1.5 mg/m2), prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in courses 1-3 and methotrexate (60 mg/m2) IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity. | Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: mercaptopurine<br>* Given by mouth<br>Drug: methotrexate<br>* Given IV and intrathecally<br>Drug: prednisone<br>* Given by mouth<br>Drug: vincristine sulfate<br>* Given IV<br>|
| Experimental: Consolidation with Vinblastine<br>In courses 1-3, patients receive doxorubicin hydrochloride (30 mg/m2) IV, methotrexate (age adjusted dosing) IT, prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in arm I and vinblastine sulfate (4 mg/m2) IV over 1 minute on days 1, 8, and 15. In courses 4 and 5, patients receive doxorubicin hydrochloride (30 mg/m2) IV, prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in arm I and vinblastine sulfate (4 mg/m2) as in arm II (courses 1-3). In courses 6-15, patients receive prednisone (120 mg/m2/day) and mercaptopurine (225 mg/m2) as in arm I, vinblastine sulfate (4 mg/m2) IV as in arm II (courses 1-3), and methotrexate (60 mg/m2) IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity. | Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: mercaptopurine<br>* Given by mouth<br>Drug: methotrexate<br>* Given IV and intrathecally<br>Drug: prednisone<br>* Given by mouth<br>Drug: vinblastine sulfate<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | Percentage of EFS patients. This is measured as the time from study entry until disease progression, disease recurrence, occurrence of a second malignant neoplasm, or death from any cause. To measure Event Free Survival, repeated one-sided logrank tests will be performed The upper critical values are based on the one-sided alpha-spending functions of t2 (alpha=0.05) and the lower critical values are based on testing the alternative hypothesis at 0.005 level. | From first enrollment up to 3 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anaplastic large cell lymphoma