Sorafenib in Treating Patients With Advanced Malignant Solid Tumors

OBJECTIVES:

Primary

- To evaluate the feasibility of re-escalating the dose of sorafenib tosylate in patients
with advanced malignant solid tumors who initially required a dose reduction for
toxicity, and dose escalation in those patients who are able to tolerate the initial
dose.

Secondary

- To evaluate the efficacy of this drug in these patients who are able to tolerate a dose
escalation initially or after a dose reduction compared to those who are unable to
tolerate a dose escalation.

Tertiary

- To evaluate the percentage and demographic characteristics of patients who are able to
tolerate 2 dose escalations without a dose reduction.

OUTLINE: This is a dose-finding study.

- Course 1: Patients receive oral sorafenib tosylate twice daily at dose level 0 on weeks
1-4.

- Course 2: Patients experiencing no dose-limiting or intolerable toxicities receive oral
sorafenib tosylate at dose level +1 twice daily on weeks 5-8; while patients
experiencing dose-limiting or intolerable toxicities receive oral sorafenib tosylate at
dose level -1 once daily on weeks 5-8.

- Course 3: Depending on whether or not patients are experiencing dose-limiting or
intolerable toxicities, they are escalated to dose level 0 or dose level +2 (patients in
both dose levels receive oral sorafenib tosylate twice daily) in weeks 9-12, or
de-escalated to dose level 0 or dose level -2 (patients in dose level -2 receives oral
sorafenib tosylate once every other day) in weeks 9-12.

- Maintenance therapy: Patients receive oral sorafenib tosylate at the dose level*
attained at the end of course 3. Treatment continues in the absence of unacceptable
toxicity.

- Dose level de-escalation for toxicity or dose re-escalation after a toxicity-related
dose reduction allowed to a maximum level of the initial dose level of the maintenance
therapy.

After completion of study therapy, patients are followed for up to 1 year.

Inclusion Criteria

- Histologically or cytologically confirmed metastatic or unresectable solid tumor for
which standard curative or palliative measures do not exist or are no longer effective
or solid tumor for which sorafenib is considered acceptable therapy

- Age > 18 years old

- Performance Status 0 - 2

- Measurable or non-measurable disease.

- Adequate bone marrow, liver and renal function

- Any number of prior chemotherapy regimens are allowed.

- Any prior chemotherapy, immunotherapy or targeted therapy must have been completed at
least 2 weeks prior to start of this protocol and all side effects resolved to grade 1
or less. Any prior radiation must have been completed at least 2 weeks prior to start
of therapy.

- Women of childbearing potential must have a negative pregnancy test performed within 7
days prior to the start of treatment

- Women of childbearing potential and men must agree to use adequate contraception prior
to study entry and for the duration of study participation. Men should use adequate
birth control for at least three months after the last administration of sorafenib.

- Ability to understand and the willingness to sign a written informed consent.

- International normalized ratio < 1.5 or a Prothrombin Time/Partial thromboplastin time
within normal limits.

Exclusion Criteria

- Prior therapy with sorafenib or sunitinib.

- Cardiac disease: Congestive heart failure > class II New York Heart Association.

- Symptomatic or uncontrolled brain metastasis.

- No component of squamous carcinoma can be present in any patient with non-small cell
lung cancer

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.

- Known HIV infection or chronic Hepatitis B or C.

- Active clinically serious infection > CTCAE Grade 2.

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months.

- Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of
study drug.

- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of
study drug.

- Serious non-healing wound, ulcer, or bone fracture.

- Evidence or history of bleeding diathesis or coagulopathy

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
dose of study drug.

- Use of St. John's Wort or rifampin

- Known or suspected allergy to sorafenib or any agent given in the course of this
trial.

- Any condition that impairs patient's ability to swallow whole pills.

- Any significant malabsorption problem.

- Therapy with bevacizumab < 3 months prior to first dose of study drug.