RATIONALE: KX2-391 may stop the growth of cancer cells by blocking some of the enzymes
needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of KX2-391 in
treating patients with advanced solid tumors or lymphoma that did not respond to treatment.
- To define the maximum tolerated dose of KX2-391 when administered as multiple oral
solutions in patients with refractory advanced solid tumors and lymphoma.
- To determine the safety and tolerability of KX2-391 given as single and multiple oral
solutions in these patients.
- To characterize the pharmacokinetic profile of single dosing and multiple dosing of
KX2-391 in these patients.
- To determine the biological effects of KX2-391.
OUTLINE: This is a multicenter study.
Patients receive oral KX2-391 once or twice daily for 3 weeks. Treatment repeats every 4
weeks in the absence of disease progression or unacceptable toxicity.
Blood and urine samples are collected periodically for pharmacokinetic studies. Biological
effects are assessed by measuring plasma levels of vascular endothelial growth factor by
ELISA. Levels of phospho-Src Tyr and transphosphorylation of selected substrates are
measured in peripheral blood mononuclear cells.
- Confirmed diagnosis of advanced solid tumor or lymphoma
- Metastatic or unresectable disease
- Standard curative or palliative measures do not exist or are no longer effective
- Patients with treated brain or ocular metastases are eligible
- ECOG performance status 0-2
- Life expectancy ≥ 14 weeks
- ANC ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Hemoglobin ≥ 10 g/dL
- Serum bilirubin ≤ 2.5 times upper limit of normal (ULN)
- ALT and AST ≤ 2.5 times ULN
- Alkaline phosphatase ≤ 2.5 times ULN
- Serum creatinine ≤ 1.5 times ULN or creatinine clearance > 60 mL/min
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective barrier contraception for 1 month prior to,
during, and for 6 months after completion of study treatment
- No inflammatory bowel disease, malabsorption syndrome, or other medical condition
that may interfere with oral drug absorption
- No signs or symptoms of end organ failure, major chronic illnesses other than cancer,
or any severe concomitant conditions including, but not limited to, active infections
that, in the opinion of the investigator, precludes protocol participation or
- No history of any of the following within the past 6 months:
- Angina pectoris
- Coronary artery disease
- Cerebral vascular accident
- Transient ischemic attack uncontrolled by medical therapy
- No history of confirmed cardiac conduction abnormalities or arrhythmias
- No known history of hepatitis B or C, or HIV infection
- No known history of coagulation disorders or hemolytic conditions (e.g., sickle cell
PRIOR CONCURRENT THERAPY:
- Recovered from all prior therapy
- No prior major surgery to the upper gastrointestinal tract
- More than 2 weeks since prior investigational agents or systemic anticancer agents
(28 days for agents with unknown elimination half-lives or known elimination
half-lives > 50 hours)
- More than 4 weeks since prior radiotherapy to the sternum, pelvis, scapulae,
vertebrae, or skull and recovered
- More than 4 weeks since prior major surgery
- More than 1 week since prior palliative low-dose radiotherapy to the limbs and
- More than 2 weeks since prior and no concurrent hormones (e.g., estrogen
contraceptives, hormone replacement, anti-estrogen, or progesterone) or antiplatelet
- More than 2 weeks since prior and no concurrent anticoagulants (e.g., coumadin)
except prophylactic doses of anticoagulants for indwelling venous catheters
- More than 2 weeks or 5 half-lives since prior and no concurrent cytochrome P450
modulators (e.g., strong inducers or inhibitors)