Everolimus and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

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. Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Giving everolimus together with lenalidomide may be an effective treatment for lymphoma. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving everolimus and lenalidomide together and to see how well they work in treating patients with relapsed or refractory non-Hodgkin or Hodgkin lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I.Phase I: To establish the maximum tolerated dose of EVEROLIMUS and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma. II. Phase II: To assess tumor response to EVEROLIMUS and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma. SECONDARY OBJECTIVES: I. To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure of subjects receiving EVEROLIMUS and lenalidomide. II. To describe the adverse event profile (using CTCAE CTEP Version 4.0) of EVEROLIMUS and lenalidomide. OUTLINE: Patients receive oral everolimus once daily and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Official Title
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A Phase I/II Clinical Trial of the mTor Inhibitor RAD001 (Everolimus) in Combination With Lenalidomide (Revlimid) for Patients With Relapsed or Refractory Lymphoid Malignancy

Conditions
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Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Peripheral T-cell Lymphoma, Post-transplant Lymphoproliferative Disorder, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Splenic Marginal Zone Lymphoma, Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: everolimus
* Drug: lenalidomide
* Other: laboratory biomarker analysis
* Genetic: polymorphism analysis
* Other: immunohistochemistry staining method
* Genetic: microarray analysis
* Genetic: fluorescence in situ hybridization


Participation Criteria
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Eligibility Criteria
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Inclusion Histological or cytological confirmation of relapsed or refractory non-Hodgkin lymphoma or Hodgkin lymphoma =< 6 months prior to registration The following disease types are eligible: Study 1 - Aggressive lymphomas- Transformed lymphomas; Diffuse large B cell lymphoma; Mantle cell lymphoma; Follicular lymphoma grade III; Precursor B lymphoblastic leukemia/lymphoma; Mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma/leukemia; Precursor T lymphoblastic leukemia/lymphoma; Primary cutaneous anaplastic large cell lymphoma; and Anaplastic large cell lymphoma-primary systemic type Study 2- Indolent lymphomas: Follicular lymphoma, grades 1, 2; Extranodal marginal zone B-cell lymphoma of MALT type; Nodal marginal zone B-cell lymphoma; Splenic marginal zone B-cell lymphoma; Small lymphocytic lymphoma Study 3- Uncommon lymphomas: Peripheral T cell lymphoma, unspecified; Anaplastic large cell lymphoma (T and null cell type); Lymphoplasmacytic lymphoma (Waldenstrom Macroglobulinemia); Post transplant lymphoproliferative disorders; Mycosis fungoides/Sezary syndrome; Hodgkin Disease; Primary effusion lymphoma; Adult T-cell leukemia/lymphoma; Extranodal NK/T-cell lymphoma, nasal type; Enteropathy-type T-cell lymphoma; Hepatosplenic T-cell lymphoma; Subcutaneous panniculitis-like T-cell lymphoma; Angioimmunoblastic T-cell lymphoma; Anaplastic large cell lymphoma-primary cutaneous type; and Blastic plasmacytoid dendritic cell neoplasm Measurable disease by CT or MRI or PET/CT: Must have at least one lesion that has a single diameter of >= 2 cm or tumor cells in the blood >= 5 x10^9/L (Skin lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler) For lymphoplasmacytic lymphoma patients without measurable lymphadenopathy, measurable disease is defined by both of the following criteria: Bone marrow lymphoplasmacytosis with > 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy and quantitative IgM monoclonal protein > 800 mg/dL ANC >= 1200/uL Hgb > 9 g/dl PLT >= 50,000/uL Total bilirubin =< 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN the direct bilirubin must be normal AST =< 2.5 x ULN or AST =< 5 x ULN if liver involvement Creatinine =< 1.5 x ULN Creatinine clearance >= 50mL/min (Cockcroft-Gault calculation) Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN (NOTE: Lipid lowering medication is allowed) ECOG Performance Status (PS) 0, 1, or 2 Females of childbearing potential (FCBP) must have a negative serum pregnancy test with a sensitivity of at least 50 IU/ml within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide, during study treatment and for 8 weeks after the last dose of RAD001 (FCBP must also agree to ongoing pregnancy testing) Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy (All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure) Provide informed written consent Willingness to return to Mayo Clinic enrolling institution for follow-up Patient is willing to provide blood samples for research purposes Recovered from acute side effects of prior myelosuppressive chemotherapy or biological therapy All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist Exclusion Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Active other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of the cervix (If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer) History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; Nursing women; Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the study and for 8 weeks after the last dose of study drug (NOTE: If barrier contraceptives are being used, these must be continued throughout the trial by both sexes; hormonal contraceptives are not acceptable as a sole method of contraception) Patients who have received prior treatment with both an mTOR inhibitor (sirolimus, temsirolimus, everolimus) and lenalidomide who did not have a response to either when used as single agents Patients with a known allergic reaction to thalidomide, RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or their excipients to the point where either agent should not be given again The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs Known positive for HIV or infectious hepatitis, type A, B or C Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study Immunization with attenuated live vaccines within one week of study entry or during study period Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) Prior Allogeneic Stem Cell Transplant No chronic treatment with systemic steroids or another immunosuppressive agents (at a dose equivalent of greater than 20 mg prednisone per day) or other immunosuppressive agents)

Ages Eligible for Study
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Minimum Age: 18 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: Arm I<br>Patients receive oral everolimus once daily and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. | Drug: everolimus<br>* Given orally<br>* Other names: RAD001;Drug: lenalidomide<br>* Given orally<br>* Other names: Revlimid;Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: polymorphism analysis<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Optional correlative studies<br>* Other names: immunohistochemistry;Genetic: microarray analysis<br>* Optional correlative studies<br>* Other names: gene expression profiling;Genetic: fluorescence in situ hybridization<br>* Optional correlative studies<br>* Other names: fluorescence in situ hybridization (FISH);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Reporting Dose-Limiting Toxicity (DLT) (Phase I) | The number of dose-limiting toxic events (DLT) for this combination of drug treatment will determine the Maximum Tolerated Dose (MTD) in subsequent phases of this study. The following events were defined as a DLT: a grade 4+ Neutropenia or platelet count decrease, a grade 4 infection, or any grade 3+ non-hematologic event as assessed using Common Terminology Criteria for Adverse Events (CTCAE) CTEP Version 4.0. Here, the number of patients reporting a DLT are reported | After one 28 day cycle | 
| Best Response to Dose Level 0 | Patients were assessed using the Cheson et al. Revised Response Criteria for Malignant Lymphoma (Cheson, et al 2007). A Complete Response (CR) was defined as the disappearance of all evidence of disease, no palpable nodules and bone marrow cleared on biopsy. A Partial Response (PR) was defined as regression of measureable disease and no new sites, with a 50% decrease in sum of the products of dimension (SPD) of nodal masses, and no increase in spleen or liver size. Patients with Waldenstrom's Macroglobulinemia were eligible to be evaluated as a Minor Response (MR) in which a reduction between 25% and 50% of serum monoclonal IgM was observed. A Progression (PD) was defined as having any new lesions or a 50% increase in the SPD of any previously involved nodes. A Stable Disease (SD) is the absence of any of the previously defined responses. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival for All Eligible Patients | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Up to 5 years | 
| Progression-Free Survival For All Eligible Patients | Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier. | Up to 5 years | 
| Duration of Response for All Eligible Patients | Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest objective status is first noted to be either a CR or PR to the earliest date progression is documented. | Up to 5 years | 
| Time to Treatment Failure for All Eligible Patients | Time to treatment failure is defined to be the time from registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier. | Up to 5 years |