Campath-1H and EPOCH to Treat Non-Hodgkin's T- and NK-Cell Lymphomas

Study Overview
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Brief Summary
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Background: The paradigm of combining therapeutic agents with non-overlapping toxicities for the treatment of malignancy produces clinical remissions and cures in a number of tumor types. A new class of agents, humanized and chimerized monoclonal antibodies, typically have little or no hematopoietic toxicity and can be readily combined with full doses of cytotoxic chemotherapy. It has become clear that in certain lymphomas and breast cancers, the combination of monoclonal antibodies and chemotherapy improves response rate and the quality of the response compared with that achieved by treatment with either agent alone. The clinical outcome for patients with T-cell non-Hodgkins lymphoma is significantly inferior to the outcome of patients with B-cell non-Hodgkin s lymphoma. In most reports less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 years. Objectives: Determine the toxicity of Alemtuzumab and etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) chemotherapy in untreated cluster of differentiation 52 (CD52)-expressing T and natural killer (NK) lymphoid malignancies. Determine the maximum tolerated dose of Alemtuzumab administered in combination with EPOCH chemotherapy. Determine in a preliminary fashion the anti-tumor activity of the combination of Alemtuzumab and EPOCH chemotherapy. Eligibility: CD52-expressing lymphoid malignancy. Patients with chemotherapy naive aggressive T & NK lymphomas. Patients with alk-positive anaplastic large cell lymphoma and patients with T cell precursor disease are not eligible. Age greater than or equal to 17 years. Adequate organ function, unless impairment due to respective organ involvement by tumor. No active symptomatic ischemic heart disease, myocardial infarction or congestive heart. failure within the past year. Human immunodeficiency virus (HIV) negative. Not pregnant or nursing. Design: Three dose levels of Alemtuzumab will be evaluated to determine the toxicity profile and in a preliminary fashion the antitumor activity of the combination with Dose-Adjusted EPOCH. Three dose levels of Alemtuzumab will be explored, in cohorts of three to six patients each. Patients will receive either 30, 60, or 90 mg of Alemtuzumab on day 1 of therapy, followed by dose-adjusted EPOCH chemotherapy days 1-5.

Detailed Description
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Background: The paradigm of combining therapeutic agents with non-overlapping toxicities for the treatment of malignancy produces clinical remissions and cures in a number of tumor types. A new class of agents, humanized and chimerized monoclonal antibodies, typically have little or no hematopoietic toxicity and can be readily combined with full doses of cytotoxic chemotherapy. It has become clear that in certain lymphomas and breast cancers, the combination of monoclonal antibodies and chemotherapy improves response rate and the quality of the response compared with that achieved by treatment with either agent alone. The clinical outcome for patients with T-cell non-Hodgkins lymphoma is significantly inferior to the outcome of patients with B-cell non-Hodgkins lymphoma. In most reports less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 years. Objective: Determine the toxicity and maximum tolerated dose (MTD) of Alemtuzumab and EPOCH chemotherapy in untreated cluster of differentiation 52 (CD52)-expressing T and natural killer (NK) lymphoid malignancies Eligibility: CD52-expressing lymphoid malignancy. Patients with chemotherapy naive aggressive T & NK lymphomas. Patients with alk-positive anaplastic large cell lymphoma and patients with T cell precursor disease are not eligible. Age greater than or equal to 17 years. Adequate organ function, unless impairment due to respective organ involvement by tumor. No active symptomatic ischemic heart disease, myocardial infarction or congestive heart. failure within the past year. Human immunodeficiency virus (HIV) negative. Not pregnant or nursing. Design: Three dose levels of Alemtuzumab will be evaluated to determine the toxicity profile and in a preliminary fashion the antitumor activity of the combination with Dose-Adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH). Three dose levels of Alemtuzumab will be explored, in cohorts of three to six patients each. Patients will receive either 30, 60, or 90 mg of Alemtuzumab on day 1 of therapy, followed by dose-adjusted EPOCH chemotherapy days 1-5.

Official Title
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Phase 2 Trial of Alemtuzumab and Dose-Adjusted Epoch in Chemotherapy Naive Aggressive T and NK-Cell Lymphomas

Conditions
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Lymphoma, T-Cell, Lymphoma, Extranodal NK-T-Cell

Intervention / Treatment
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* Biological: Alemtuzumab (Campath)
* Drug: EPOCH


Participation Criteria
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Eligibility Criteria
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ELIGIBILITY CRITERIA: Cluster of differentiation 52 (CD52)-expressing lymphoid malignancy, confirmed by pathology or flow cytometry staff of the Hematopathology Section, Laboratory of Pathology, National Cancer Institute (NCI). Patients with T & natural killer (NK) cell malignancy without accessible tissue for flow cytometry analysis may be treated on this study. Patients with chemotherapy naive aggressive T & NK lymphomas, including but not limited to peripheral T cell lymphoma (not otherwise specified (nos)), gamma-delta hepatosplenic T cell lymphoma, subcutaneous panniculitis-like T cell, NK-T cell lymphoma confirmed by pathology or flow cytometry staff of the Hematopathology Section, Laboratory of Pathology, NCI. Patients with alk-positive anaplastic large cell lymphoma and patients with T cell precursor disease are not eligible. Age greater than or equal to 17 years. Laboratory tests: Creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 ml/min; bilirubin less than 2.0 mg/dl unless due to Gilbert's, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 times upper limit of normal (ULN) (AST and ALT is less than or equal to 6 times ULN for patients on hyperalimentation for whom these abnormalities are felt to be due to the hyperalimentation) and; absolute neutrophil count (ANC) is greater than or equal to 1000/mm(3), platelet greater than or equal to 75,000/mm(3); unless impairment due to respective organ involvement by tumor. No active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. Human immunodeficiency virus (HIV) negative, because of the unknown effects of combined therapy with chemotherapy and an immunosuppressive agent on HIV progression. Signed informed consent. Willing to use contraception. Not pregnant or nursing, because of the unknown effects of Alemtuzumab on the developing fetus and infant. No serious underlying medical condition or infection that would contraindicate treatment. Patients with central nervous system (CNS) involvement are eligible for treatment on this study.

Ages Eligible for Study
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Minimum Age: 17 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: Alemtuzumab Dose Escalation<br>Alemtuzumab (Campath) followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) every 3 weeks for up to 6 cycles. Three cohorts of 3 to 6 patients will be treated. Cohort 1 will receive 30mg of Alemtuzumab, cohort 2 will receive 60mg of Alemtuzumab, and cohort 3 will receive 90mg of Alemtuzumab. If 1 of 3 participants entered at a given dose level experiences dose limiting toxicity (DLT), up to 3 additional participants will be entered at that dose level. If 2 of 6 participants experience DLT at a particular dose level, the maximum tolerated dose (MTD) has been exceeded. The preceding dose level will be the MTD, provided 6 participants have been entered at this level and no more than 1 has experienced DLT. | Biological: Alemtuzumab (Campath)<br>* Alemtuzumab (Campath) followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) every 3 weeks for up to 6 cycles.<br>* Other names: Campath;Drug: EPOCH<br>* Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) + Alemtuzumab (Campath) every 3 weeks for up to 6 cycles.<br>* Other names: Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Alemtuzumab | MTD was achieved by increasing doses of Alemtuzumab on three cohorts. Cohort 1 received 30mg of Alemtuzumab, cohort 2 received 60mg of Alemtuzumab, and cohort 3 received 90mg of Alemtuzumab intravenously up to 2 cycles. The MTD reflects the highest dose of Alemtuzumab in which no more than 1 of 6 participants entered at a specific dose level experienced a dose limiting toxicity (DLT). | up to 2 cycles of therapy, approximately 42 days | 
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 67 months and 9 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | Response was measured by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease. Complete response unconfirmed (Cru)is as per complete remission criterion except that if a residual node is greater than 1.5cm, it must have decreased by greater than 75% in the sum of the products of the perpendicular diameters (SPD). Partial response (PR) is ≥50% decrease in the SPD of 6 largest dominant nodes or nodal masses. Progressive disease (PD) is ≥50% increase from the nadir in the SPD of any previously identified abnormal node for PRS or non-responders. Stable disease (SD) is less than a PR but not progressive disease. | From date of onstudy until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 67 months and 9 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, T-Cell Lymphoma, NK -Cell Lymphoma