Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

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.

Further Study Information

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 this 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 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• 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.

Eligibility Criteria

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

Trial Contact Information

Trial Lead Organizations/Sponsors

Mayo Clinic Cancer Center

Thomas E. Witzig

Principal Investigator

Shaji K. Kumar

Principal Investigator

U.S.A.
Iowa
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Cancer Information Service	Ph: 800-237-1225
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph: 507-538-7623

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00474929
Information obtained from ClinicalTrials.gov on August 05, 2012

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