RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
so they stop growing or die. Combining more than one drug may kill more cancer cells.
PURPOSE: Phase I trial to study the effectiveness of combining paclitaxel and L-778,123 in
treating patients who have recurrent or refractory solid tumors or lymphomas.
OBJECTIVES: I. Determine the maximum tolerated dose of L-778,123 when combined with
paclitaxel in patients with recurrent or refractory solid tumors or lymphomas. II. Evaluate
the safety, tolerability, and dose limiting toxicity of this regimen in these patients. III.
Assess steady state plasma concentrations of various doses of L-778,123 combined with
paclitaxel in these patients. IV. Evaluate radiologic or tumor marker responses to this
regimen in these patients. V. Evaluate the relationship between ras mutations and response
to this regimen in these patients.
OUTLINE: This is a dose escalation, multicenter study of L-778,123. Patients receive
paclitaxel IV over 3 hours followed within 24 hours by L-778,123 IV over 7 days. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients achieving complete response receive 2 courses after documentation of response.
Cohorts of 1-3 patients receive escalating doses of L-778,123 until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 patients experience
dose limiting toxicity. Patients are followed at about 2 weeks.
PROJECTED ACCRUAL: A maximum of 40 patients will be accrued for this study.
DISEASE CHARACTERISTICS: Histologically proven solid tumor or lymphoma that is recurrent
or refractory to standard first line therapy Measurable or evaluable disease No active or
inactive primary CNS malignancy No untreated active metastatic CNS malignancy No leukemia
or plasma cell dyscrasias
PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-2 Life expectancy:
Greater than 3 months Hematopoietic: Absolute neutrophil count at least 1,500/mm3 Platelet
count at least 100,000/mm3 Hemoglobin at least 9 g/dL Hepatic: Bilirubin no greater than
1.5 times normal ALT or AST no greater than 2.5 times normal Alkaline phosphatase no
greater than 4 times normal (no greater than 2 times normal if an increase of greater than
25% over past 2 weeks) PT, INR, or aPTT no greater than 1.2 times normal Renal: Creatinine
no greater than 1.5 times normal Electrolytes within 10% of normal range Cardiovascular:
No prior grade 3 or 4 cardiac arrhythmias except atrial fibrillation No QTc interval of
440 milliseconds or greater on electrocardiogram No other QTc abnormalities No myocardial
infarction, unstable angina, or congestive heart failure within the past 12 months
Psychiatric: No mental or legal incapacitation No concurrent significant emotional
problems No prior psychiatric disorder Neurologic: No grade 2 or higher peripheral
neuropathy No prior seizure disorder Other: Not pregnant or nursing Negative pregnancy
test Fertile patients must use effective double barrier contraception or practice
abstinence for at least 14 days before, during, and for at least 14 days after therapy No
allergy to latex, Cremophor (found in formulations of cyclosporine or vitamin K), or
paclitaxel HIV negative No HIV related malignancy No active infection No prior significant
retinal disorder or disease At least 5 years since prior drug or alcohol abuse
PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 weeks since prior immunotherapy No
concurrent immunotherapy No concurrent colony stimulating factors or epoetin alfa
Chemotherapy: At least 4 weeks since prior chemotherapy (6 weeks for mitomycin and
nitrosoureas) At least 4 weeks since prior paclitaxel and recovered No prior high dose
chemotherapy with stem cell rescue No other concurrent chemotherapy Endocrine therapy: At
least 4 weeks since prior endocrine therapy (except chronic LHRH agonist replacement
therapy administered for at least 3 months) No concurrent endocrine therapy except
prophylactic steroids during first course of chemotherapy Radiotherapy: At least 4 weeks
since prior radiotherapy No concurrent radiotherapy Surgery: At least 4 weeks since prior
surgery No concurrent surgery Permanent indwelling central venous catheter required Other:
At least 4 weeks since prior investigational agents (including FDA approved drugs for
non-FDA approved indication) No concurrent medications that prolong QTc interval (e.g.,
terfenadine, astemizole, cisapride, quinidine, procainamide, disopyramide, sotalol,
probucol, bepridil, tricyclic antidepressants, haloperidol, risperidone, indapamide, and
dolasetron mesylate) No concurrent potent inducers of CYP3A (e.g., rifampin,
phenobarbital, phenytoin, carbamazepine, troglitazone, and rifabutin) No concurrent
benzodiazepines that are metabolized by CYP3A (e.g., triazolam, alprazolam, and midazolam)
No concurrent HMG-CoA reductase inhibitors that are metabolized by CYP3A No other
prophylactic medications during first course of chemotherapy except antihistamines and H2
antagonists (for paclitaxel) No more than 6 cups of coffee or the equivalent for other
caffeinated beverages per day At least 24 hours since prior alcohol consumption No alcohol
consumption while confined to the clinical research unit No more than 24 ounces of beer, 8
ounces of wine, or 3 ounces of whiskey or other equivalent hard liquor per day while not
confined to the clinical research unit No concurrent illicit drugs No concurrent