Everolimus in Treating Patients With Lymphoma That Has Relapsed or Not Responded to Previous Treatment

Study Overview
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Brief Summary
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RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. PURPOSE: This phase II trial is studying the side effects and how well everolimus works in treating patients with lymphoma that has relapsed or not responded to previous treatment.

Detailed Description
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OBJECTIVES: Primary Assess the tumor response in patients with relapsed or refractory indolent non-Hodgkin lymphoma (closed to accrual as of 8/18/08), aggressive non-Hodgkin's lymphoma (closed to accrual as of 2/7/08 except for diffuse large B cell lymphoma, grade III follicular lymphoma, or transformed lymphoma), or uncommon lymphoma (closed to accrual as of 9/2/08), including Hodgkin's lymphoma, treated with everolimus. Secondary Evaluate overall survival, progression-free survival, and time to disease progression in patients treated with this drug. OUTLINE: This is a multicenter study. Patients are stratified according to histology (aggressive lymphoma [closed to accrual as of 2/7/08 except for diffuse large B cell lymphoma, grade III follicular lymphoma, or transformed lymphoma] vs indolent lymphoma [closed to accrual as of 8/18/08] vs uncommon lymphoma [closed to accrual as of 9/2/08]). Patient receive oral everolimus daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tissue collection at baseline and periodically during study treatment for translational research studies. Blood and tissue samples are analyzed for biomarkers to study the effect of everolimus on lymphoma. After completion of study treatment, patients are followed periodically for up to 5 years.

Official Title
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Phase II Trial of Everolimus (RAD001) in Relapsed/Refractory Lymphoma

Conditions
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Leukemia, Lymphoma, Lymphoproliferative Disorder

Intervention / Treatment
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* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy-proven* relapsed or refractory lymphoma, including the following: Aggressive lymphoma (closed to accrual as of 2/7/08 except for diffuse large B cell lymphoma, grade III follicular lymphoma, or transformed lymphoma) Transformed lymphoma Diffuse large B-cell lymphoma Mantle cell lymphoma Grade 3 follicular lymphoma Precursor B-cell lymphoblastic leukemia/lymphoma Mediastinal (thymic) large B-cell lymphoma Burkitt's lymphoma/leukemia Precursor T-cell lymphoblastic leukemia/lymphoma Primary cutaneous anaplastic large cell lymphoma Primary systemic type anaplastic large cell lymphoma Indolent lymphoma (closed to accrual as of 8/18/08) Small lymphocytic lymphoma/chronic lymphocytic leukemia Grade 1 or 2 follicular lymphoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma Splenic marginal zone B-cell lymphoma Uncommon lymphoma (closed to accrual as of 9/2/08) Unspecified peripheral T-cell lymphoma Anaplastic large cell lymphoma (T and null cell type) Lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia) Central Nervous System (CNS) lymphoma Post-transplant lymphoproliferative disorder Mycosis fungoides/Sezary syndrome Hodgkin's lymphoma Primary effusion lymphoma Blastic Natural Killer(NK)-cell lymphoma Adult T-cell leukemia/lymphoma Nasal type extranodal NK/T-cell lymphoma Enteropathy type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Angioimmunoblastic T-cell lymphoma NOTE: *Biopsies performed < 6 months prior to study entry are allowed; biopsy-proven CNS lymphoma (at any time) does not require a re-biopsy in order to be eligible for this study Previously treated disease Patients with aggressive lymphoma (closed to accrual as of 8/24/07) OR Hodgkin's lymphoma must have received or be ineligible for potentially curative therapy, including stem cell transplantation Measurable disease** by CT scan or MRI, defined by 1 of the following: At least 1 unidimensionally measurable lesion > 2 cm in diameter Skin lesions may be used if they meet this criterion and are photographed with a ruler More than 5,000/mm³ tumor cells in the blood NOTE: **For patients with lymphoplasmacytic lymphoma without measurable lymphadenopathy, measurable disease may be defined by bone marrow lymphoplasmacytosis with > 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy AND quantitative Immunoglobulin M(IgM) monoclonal protein > 1,000 mg/dL PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group(ECOG) performance status 0-2 Life expectancy > 3 months Absolute neutrophil count ≥ 1,000/mm³ Platelet count ≥ 75,000/mm³ Hemoglobin ≥ 8 g/dL Total bilirubin ≤ 2 times upper limit of normal (ULN) OR direct bilirubin ≤ 1.5 times ULN aspartate aminotransferase(AST) ≤ 3 times ULN (5 times ULN if liver involvement is present) Creatinine ≤ 2 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing to provide blood samples and portion of bone marrow aspirate and biopsy during study participation Able to swallow intact study medication tablets No other life-threatening illness (unrelated to tumor) No serious non-malignant disease (e.g., active infection or other condition) that, in the opinion of the investigator, would preclude study participation No other active malignancy requiring treatment or that would preclude study participation No known HIV positivity PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 3 weeks since prior myelosuppressive chemotherapy or biologic therapy (unless the patient has recovered from the nadir of the previous treatment) More than 3 weeks since prior radiotherapy (unless the acute side effects associated with therapy are resolved) Concurrent stable (i.e., not increased within the past month) chronic doses of corticosteroids, with a maximum dose of 20 mg of prednisone per day, is allowed if prescribed for disorders other than lymphoma (e.g., rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, or asthma) Non-escalating doses of steroids at the lowest possible dosing level are allowed for CNS lymphoma No other concurrent investigational ancillary therapy No other concurrent chemotherapy, immunotherapy, or radiotherapy No concurrent participation in any other clinical trial involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy, or gene therapy) for symptom control or therapeutic intent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relapsed aggressive non-Hodgkin lymphoma<br>Study 1. Everolimus 10 mg orally daily for 4 week cycle. Repeat until progression, unacceptable toxicity, refusal, or alternative therapy at any time. | Drug: Everolimus<br>* Everolimus 10 mg orally daily for 4 week cycle. Repeat until progression, unacceptable toxicity, refusal, or alternative therapy at any time.<br>* Other names: Mayo abbreviation: RAD001;|
| Experimental: Relapsed indolent non-Hodgkin lymphoma<br>Study 2. Everolimus 10 mg orally daily for 4 week cycle. Repeat until progression, unacceptable toxicity, refusal, or alternative therapy at any time. | Drug: Everolimus<br>* Everolimus 10 mg orally daily for 4 week cycle. Repeat until progression, unacceptable toxicity, refusal, or alternative therapy at any time.<br>* Other names: Mayo abbreviation: RAD001;|
| Experimental: Uncommon lymphomas<br>Study 3. Includes Hodgkin's lymphomas. Everolimus 10 mg orally daily for 4 week cycle. Repeat until progression, unacceptable toxicity, refusal, or alternative therapy at any time. | Drug: Everolimus<br>* Everolimus 10 mg orally daily for 4 week cycle. Repeat until progression, unacceptable toxicity, refusal, or alternative therapy at any time.<br>* Other names: Mayo abbreviation: RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response, Defined by Disease: Chronic Lymphocytic Leukemia(CLL): Clinical Complete or Complete or Nodular Partial or Partial Remission, Waldenstrom: Complete or Partial Response, All Others: Complete or Complete Unconfirmed or Partial Response. | CLL (subset of patients in the Relapsed Indolent Non-Hodgkin Lymphoma group): 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions. Waldenstrom (subset of patients in the Uncommon Lymphomas group): >50% reduction in serum immunoglobulin M(IgM) levels (by serum protein electrophoresis (SPEP)) during any point while in this study, and no appearance of new lesions. All others: at least a 50% decrease in the sum of the products of the greatest diameters (SPD) of the six largest dominant nodes or nodal masses and no increase in the size of other nodes, liver, or spleen and splenic and hepatic nodules must regress by at least 50% in the SPD and no new sites of disease. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The overall survival or survival time is defined as the time from registration to death due to any cause. The distribution of overall survival was estimated using the method of Kaplan-Meier. | 5 years | 
| Progression-free Survival | Progression-free survival is defined as the time from registration to the time of progression or death due to any cause. Progression-free survival was estimated using the method of Kaplan-Meier. Progression is defined as the following: CLL (subset of patients in the Relapsed Indolent Non-Hodgkin Lymphoma group): >=50% increase in nodes from nadir or >=50% increase in liver/spleen size from nadir. Waldenstrom (subset of patients in the Uncommon Lymphomas group): >50% lymph node increase in SPD of > 1 node or new nodes, or >50% liver/spleen size increase, or > 25% IgM (by SPEP) increase, or lymphocyte morphology transformation to a more aggressive histology. All Others: New lesions or >=50% lymph nodes. | 5 years | 
| Time to Progression | The time to progression is defined as the time from registration to the time of progression. The distribution of time to progression was estimated using the method of Kaplan-Meier. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult Burkitt lymphoma, recurrent adult Hodgkin lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, small intestine lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent grade 3 follicular lymphoma, recurrent marginal zone lymphoma, refractory chronic lymphocytic leukemia, recurrent small lymphocytic lymphoma, recurrent mycosis fungoides/Sezary syndrome, adult nasal type extranodal NK/T-cell lymphoma, Waldenstrom macroglobulinemia, recurrent adult diffuse large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent mantle cell lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma, post-transplant lymphoproliferative disorder, recurrent adult diffuse small cleaved cell lymphoma