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

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.

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