Sorafenib in Treating Patients With Advanced Solid Tumors
Sorafenib in Treating Patients With Advanced Solid Tumors
This randomized phase I trial is studying the side effects, such as high blood pressure, and
 best dose of sorafenib in treating patients with advanced solid tumors. Sorafenib may stop
 the growth of tumor cells by blocking some of the enzymes needed for cell growth and by
 blocking blood flow to the tumor.
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