Sorafenib and Everolimus in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Sorafenib and everolimus may stop the growth of cancer cells by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I/II trial is studying the side effects and best dose of sorafenib and everolimus and to see how well they work in treating patients with relapsed or refractory non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose (MTD) of sorafenib tosylate and everolimus in patients with relapsed or refractory non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma. Determine the toxicity of this regimen in these patients. Evaluate the therapeutic activity of this regimen in these patients. Evaluate the pharmacokinetic interaction of this regimen. Correlate clinical (toxicity and/or tumor response or activity) effects with pharmacologic (pharmacokinetic/pharmacodynamic) parameters and/or biologic (correlative laboratory) results. OUTLINE: This is a multicenter, dose-escalation, phase I study followed by a phase II study. Phase I (closed to accrual as of 2/10/2009): Patients receive oral sorafenib tosylate and oral everolimus on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sorafenib tosylate and everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 out of at most 6 patients experience a Dose Limiting Toxicity (DLT). Phase II: Patients receive oral sorafenib tosylate twice daily and oral everolimus once daily at the MTD determined in phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood and bone marrow are collected periodically during the study and analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Patients enrolled in phase I also undergo blood sample collection on days 8 and 15 during course 1 and on day 1 of each subsequent course for pharmacokinetic studies. After completion of study treatment, patients are followed every 6 months for 3 years. PROJECTED ACCRUAL: A total of 103 patients will be accrued for this study.

Official Title
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A Phase I/II Study of the Raf Kinase/VEGFR Inhibitor Sorafenib in Combination With the mTOR Inhibitor RAD001 (Everolimus) in Patients With Relapsed Non-Hodgkin Lymphoma, Hodgkin Lymphoma, or Multiple Myeloma

Conditions
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Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: RAD001
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed diagnosis of 1 of the following: Multiple myeloma Non-Hodgkin's lymphoma Hodgkin's lymphoma Relapsed or refractory disease Measurable disease, as defined according to diagnosis as follows: Multiple myeloma, meeting 1 of the following criteria: Serum monoclonal protein ≥ 1.0 g/dL Urine monoclonal protein ≥ 200 mg by 24-hour electrophoresis Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease) Lymphoma, meeting 1 of the following criteria: Measurable disease by CT scan or MRI or PET/CT scan, defined as ≥ 1 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 ≥ 1 diameter and photographed with a ruler Lymphoplasmacytic lymphoma without measurable lymphadenopathy, meeting 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 Quantitative IgM monoclonal protein > 1,000 mg/dL Not a candidate for known standard potentially curative therapy PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 12 weeks ANC ≥ 1,500/mm³ Hemoglobin ≥ 9 g/dL Platelet count ≥ 75,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal AST ≤ 3 times ULN (5 times ULN if liver involvement) Creatinine ≤ 2.5 times ULN INR < 1.5 or activated PTT < 1.5 times ULN (no concurrent anticoagulants) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for at least 2 weeks after completion of study treatment No uncontrolled infection No NYHA class III-IV congestive heart failure No unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) No myocardial infarction within the past 6 months No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management No known HIV positivity No other active malignancy requiring treatment No inability to swallow No gastrointestinal (GI) function impairment or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection) or preclude use of oral medications No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months No pulmonary hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks No severe or uncontrolled medical conditions or other conditions that would preclude study compliance No liver disease, such as cirrhosis, chronic hepatitis or chronic persistent hepatitis, or uncontrolled infections No serious nonhealing wound, ulcer, or bone fracture No evidence or history of serious bleeding diathesis or coagulopathy, such as hemophilia or von Willebrand's disease No significant traumatic injury within the past 4 weeks No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) PRIOR CONCURRENT THERAPY: More than 3 weeks since prior myelosuppressive chemotherapy or biological therapy and recovered More than 4 weeks since prior major surgery or open biopsy Lymph node biopsy within past 4 weeks allowed Prior everolimus allowed No concurrent immunosuppressant therapy Concurrent stable chronic doses of steroids (≤ 20 mg of prednisone per day) for disorders other than lymphoma (i.e., rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, asthma) or for pruritus or fever associated with lymphoma allowed Concurrent corticosteroids at the lowest possible dose necessary to control symptoms in patients with CNS lymphoma allowed No concurrent CYP450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort) No other concurrent immunotherapy, radiotherapy, or chemotherapy No concurrent chronic oxygen therapy No concurrent warfarin or heparin No other concurrent investigational therapy

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple Myeloma<br>Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day; Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day; Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day; Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day; Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day; | Drug: RAD001<br>* Phase I: Dose level 0: RAD001 5mg every other day; Dose level 1: RAD001 5mg every day; Dose level 2: RAD001 5mg every day; Dose level 3: RAD001 10mg every day; Phase II: RAD001 5mg every day;<br>* Other names: Everolimus;Drug: Sorafenib<br>* Phase I: Dose level 0: Sorafenib 200 mg twice daily; Dose level 1: Sorafenib 200 mg twice daily; Dose level 2: Sorafenib 400 mg twice daily; Dose level 3: Sorafenib 400 mg twice daily; Phase II: Sorafenib 200 mg twice daily;<br>* Other names: sorafenib tosylate;|
| Experimental: Lymphoma<br>Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day; Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day; Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day; Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day; Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day; | Drug: RAD001<br>* Phase I: Dose level 0: RAD001 5mg every other day; Dose level 1: RAD001 5mg every day; Dose level 2: RAD001 5mg every day; Dose level 3: RAD001 10mg every day; Phase II: RAD001 5mg every day;<br>* Other names: Everolimus;Drug: Sorafenib<br>* Phase I: Dose level 0: Sorafenib 200 mg twice daily; Dose level 1: Sorafenib 200 mg twice daily; Dose level 2: Sorafenib 400 mg twice daily; Dose level 3: Sorafenib 400 mg twice daily; Phase II: Sorafenib 200 mg twice daily;<br>* Other names: sorafenib tosylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting a Dose Limiting Toxicity (DLT) | The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). Dose-limiting toxicity (DLT) is defined as an adverse event attributed (definitely, probably, or possibly) in first cycle to the study treatment and meeting the following criteria: Grade 4 infection Grade 4 ANC or PLT Grade 3 or higher non-hematologic adverse event. NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 will be used to assess adverse events. For this endpoint, the number of patients reporting a DLT event are tabulated. | First cycle (28 days) of study treatment | 
| Proportion of Confirmed Tumor Responses | A confirmed response is defined to be a CR or PR noted as the objective status for eligible patients during cycles 1-12. Complete Response (CR): Multiple Myeloma (MM): Negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, and normalization of free light chain (FLC) ratio. Lymphoma: Disappearance of all clinical and radiographic evidence of disease, all lymph nodes of normal size (1.5 cm or less), no splenomegaly. Partial Response (PR): MM: 50% reduction of serum or urine M-protein or to less than 200mg/day, a 50% reduction in the difference between involved and uninvolved FLC, and 50% reduction in the size of soft tissue plasmacytoma. Lymphoma: 50% or greater reduction in sum of the products of the dimension for nodal masses; no increase in liver, spleen or node size; no new sites of disease; and a 50% decrease in lymphocyte count if followed at baseline. | Up to 12 cycles of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time | 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 3 years from registration | 
| Progression Free Survival | Progression Free Survival is defined as the time from registration to the earliest date documentation of disease progression or death. The distribution of time to disease progression will be estimated using the method of Kaplan-Meier. | Up to 3 years from registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult Hodgkin lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, stage III multiple myeloma, refractory multiple myeloma, Waldenström macroglobulinemia, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, cutaneous B-cell non-Hodgkin lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, recurrent mycosis fungoides/Sezary syndrome, recurrent adult grade III lymphomatoid granulomatosis