Phase I Pharmacokinetic Study of Dasatinib (BMS-354825) (NSC-732517; IND-73969) in Patients With Advanced Malignancies and Varying Levels of Liver Dysfunction

Inclusion Criteria:

- Histologically or cytologically confirmed solid tumor or lymphoma

- Metastatic or unresectable disease

- Standard curative or palliative measures do not exist or are no longer effective

- All solid and lymphoma tumor types are eligible

- Patients with a liver mass, elevated α-fetoprotein level (i.e., ≥ 500 ng/mL),
and positive serology for viral hepatitis consistent with a diagnosis of
hepatocellular carcinoma will be eligible without the need for pathologic
confirmation of diagnosis

- Measurable or nonmeasurable disease

- Patients with brain metastases requiring corticosteroids must be on a stable or
decreasing dose of corticosteroids

- Prior brain irradiation (whole brain or gamma knife) is required for known brain
metastases

- No untreated (non-irradiated) brain metastases

- No clinically significant pleural effusion, fluid retention, or pericardial effusion

- Patients with a history of pleurodesis and pleural effusion (malignant or
non-malignant) may be eligible but will be treated with caution

- Patients with a history of ascites are eligible

- Zubrod performance status 0-2

- Life expectancy ≥ 2 months

- Absolute neutrophil count ≥ 1,500/mm³

- Platelets ≥ 100,000/mm³

- Magnesium ≥ lower limit of normal (LLN)

- Potassium ≥ LLN

- Creatinine ≤ 1.5 times upper limit of normal OR creatinine clearance ≥ 60 mL/min

- Patients with abnormal liver function are eligible

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Patients with biliary obstruction for which a shunt has been placed are eligible
provided the liver function tests have stabilized

- Two measurements at least 2 days apart that put the patient in the same hepatic
dysfunction stratum will be accepted as evidence of stable hepatic function

- There must be no evidence of biliary sepsis and at least 2 weeks must have
elapsed after the placement of a biliary shunt

- Must be willing to undergo pharmacokinetic sampling

- Must be able to take oral medications

- Patients may not have any clinically significant cardiovascular diseases including
the following:

- Myocardial infarction or ventricular tachyarrhythmia within 6 months

- Prolonged QTc >= 480 msec (Fridericia correction)

- Ejection fraction less than normal institutional normal

- Major conduction abnormality (unless a cardiac pacemaker is present)

- Patients with any cardiopulmonary symptoms of unknown cause should be evaluated
by a baseline echocardiogram with or without stress test as needed in addition
to EKG to rule out QTc prolongation; patients with underlying cardiopulmonary
dysfunction should be excluded from the study

- No history of allergic reaction to dasatinib or similar compounds

- No ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2, atrial fibrillation of any
grade, or QTc interval > 470 msec for females or > 450 msec for males

- No active gastrointestinal bleeding

- No diagnosis of malabsorption syndrome or significant bowel resection affecting
absorption

- No clinically significant fluid retention or pericardial effusion

- No uncontrolled serious intercurrent medical illness including, but not limited to,
any of the following:

- Ongoing or serious active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Serious cardiac arrhythmia

- Uncontrolled diarrhea

- Psychiatric illness/social situation that would limit compliance with study
requirements

- No known HIV-positivity

- Recovered from all prior therapy

- More than 7 days since prior and no concurrent H2-receptor antagonist (e.g.,
cimetidine, ranitidine, or famotidine)

- More than 7 days since prior and no concurrent proton pump inhibitors (e.g.,
omeprazole, lansoprazole, esomeprazole, or pantoprazole)

- More than 4 weeks since prior major surgical procedures

- More than 4 weeks since prior and no other concurrent or plans to receive anticancer
therapy including chemotherapy, radiotherapy, immunotherapy, or investigational
agents

- At least 2 weeks since prior targeted agents with a half-life of < 24 hours

- No prior dasatinib

- Concurrent hormone therapy for prostate carcinoma may be continued

- Concurrent bisphosphonate treatment for bone disease is permitted

- No concurrent therapeutic doses of anticoagulants

- Low dose warfarin for port prophylaxis is permitted

- No concurrent enzyme-inducing anticonvulsant medications (e.g., phenobarbital,
phenytoin, or carbamazepine)

- No concurrent prophylactic colony-stimulating factors