Sorafenib in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. Determine whether increasing the dose of sorafenib tosylate increases the plasma
steady-state concentration in patients with advanced solid tumors.

II. Determine whether increasing the dose of this drug affects blood pressure in these
patients.

SECONDARY OBJECTIVES:

I. Determine whether the variability in blood pressure elevation is due to pharmacokinetic
or pharmacodynamic variability.

II. Compare the toxicity and differences in pharmacokinetics of delivering a higher dose of
this drug per day (using two different schedules) vs delivering the currently recommended
dose of this drug.

III. Investigate mechanisms of sorafenib tosylate-induced hypophosphatemia with serial
measurements of phosphate metabolism (no longer assessed as of 4/29/2009) in these patients,
detailed baseline measurements in all patients, and detailed evaluations of patients
developing grade 3 or greater hypophosphatemia.

IV. Detect subclinical effects of this drug on measures of thyroid function. V. Identify
biomarkers predicting the categorization of patient response.

OUTLINE: This is a randomized, dose-escalation study.

Patients receive oral sorafenib tosylate twice daily on days 1-7 and once on day 8. Patients
not experiencing at least one grade 2 or higher toxicity during the initial sorafenib
treatment are randomized to 1 of 3 dose-escalated treatment arms.

ARM I: Patients receive higher-dose oral sorafenib tosylate twice daily on days 15-36.

ARM II: Patients receive standard-dose oral sorafenib tosylate three times daily on days
15-36.

ARM III: (closed to accrual as of 4/29/2009) Patients receive standard-dose oral sorafenib
tosylate twice daily on days 15-36.

In all arms, treatment repeats every 3 weeks in the absence of disease progression or
unacceptable toxicity.

Patients undergo ambulatory blood pressure monitoring at baseline, on days 7, 14, and 21,
and at 6 and 12 months. Blood samples are collected periodically throughout study and
evaluated for pharmacokinetic studies, thyroid function, serum markers, and phosphate
metabolism*. CT perfusion imaging is performed at baseline, week 6, week 12, and then every
8-12 weeks thereafter.

NOTE: * Phosphate metabolism no longer assessed as of 4/29/2009.

After completion of study treatment, patients are followed every 4 weeks for 1 year and then
every 3 months thereafter.

Inclusion Criteria:

- Histologically or cytologically confirmed malignant solid tumor

- Refractory disease for which curative or palliative measures have failed or for
which there is no known superior treatment

- No colorectal cancer or melanoma

- Measurable OR nonmeasurable disease

- Normotensive (blood pressure [BP] ≤ 140/90 mm Hg) meeting 1 of the following
criteria:

- No more than 2 attempted measurement sessions for which the documented mean
systolic BP is ≤ 140 mm Hg and the diastolic BP is ≤ 90 mm Hg

- At least 30 attempted measurement sessions for which the documented mean
systolic BP is ≤ 135 mm HG and the diastolic BP is ≤ 85 mm Hg

- Brain metastases allowed provided the following criteria are met:

- Stable neurologic status for ≥ 2 weeks after completion of definitive local
therapy (surgery or radiotherapy)

- No neurologic dysfunction that would confound the evaluation of neurologic and
other adverse events

- ECOG performance status 0-1

- Life expectancy > 12 weeks

- Age ≥ 14 years OR weight ≥ 45 kilograms (pediatric patients)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Hemoglobin ≥ 8.5 g/dL

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN (5 times ULN if there is liver involvement)

- Creatinine ≤ 1.5 times ULN

- No New York Heart Association class II-IV congestive heart failure

- No unstable angina (anginal symptoms at rest) or new-onset angina (began within the
past 3 months)

- No myocardial infarction within the past 6 months

- No ventricular arrhythmias requiring anti-arrhythmic therapy

- No thrombotic or embolic events, such as symptomatic pulmonary embolus or any
cerebrovascular accident (including transient ischemic attacks) within the past 6
months

- No pulmonary hemorrhage/bleeding event > grade 2 within the past 4 weeks

- No other hemorrhage/bleeding event > grade 3 within the past 4 weeks

- No evidence or history of bleeding diathesis or coagulopathy

- No serious nonhealing wound, ulcer, or bone fracture

- No ongoing or active infection > grade 2

- No psychiatric illness or social situation that would limit compliance with study
requirements

- No allergy to sorafenib tosylate or excipients

- No unstable condition that would jeopardize the safety of the patient and/or her/his
compliance with the study

- No significant traumatic injury within the past 4 weeks

- No condition that would impair the patient's ability to swallow whole pills or
capacity to absorb oral medications

- No seizure disorder requiring steroids or anticonvulsant therapy

- No other concurrent illness

- Recovered from prior therapy

- Prior vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., bevacizumab,
sunitinib malate, axitinib) allowed provided the following criteria are met:

- The patient's best response as measured by RECIST criteria was not progressive
disease

- If the most recent agent was a small molecule reversible inhibitor (e.g.,
sunitinib malate, cediranib, or axitinib), the patient must not have taken a
dose of the agent within 2 weeks of the baseline blood pressure session and 3
weeks of starting sorafenib tosylate

- If the most recent agent was bevacizumab or VEGF trap the patient must not have
received the most recent dose within 5 weeks of the baseline blood pressure
session and 6 weeks of starting sorafenib tosylate AND no grade 3 bleeding,
cardiovascular, skin, or thyroid toxicities on one of these previous therapies

- More than 2 weeks since prior and no concurrent radiotherapy

- At least 3 weeks since prior and no concurrent chronic epoetin alfa (or congeners)

- More than 3 weeks since prior immunotherapy or chemotherapy (6 weeks for
nitrosoureas or mitomycin C)

- More than 4 weeks since prior major surgery or open biopsy

- At least 3 weeks since prior uncharacterized herbal agents or nutritional supplements

- More than 12 weeks since prior radioimmunotherapy

- No prior sorafenib tosylate

- No prior organ allograft or allogeneic bone marrow or peripheral blood stem cell
transplantation

- Patients with a history of autologous transplant and normal bone marrow function
are eligible

- No prior cyclosporine, Hypericum perforatum (St. John's wort), or rifampin

- No other concurrent investigational agents

- No other concurrent antineoplastic therapy, including chemotherapy, except
androgen-ablating agents (for patients with prior prostate cancer)

- No concurrent hematopoietic growth factors

- No concurrent combination antiretroviral therapy for HIV-positive or chronic
hepatitis B-positive patients

- No concurrent hormonal therapy except steroids for adrenal insufficiency or hormones
for nondisease-related conditions (e.g., insulin for diabetes)

- Steroids for autoimmune cytopenia allowed provided dose has been stable for 3
weeks

- No anticipated need for other antineoplastic therapy within the next 4 weeks