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.

Condition	Treatment or Intervention	Phase
Cancer	Drug: L-778,123  Drug: L-778,123/paclitaxel  Drug: paclitaxel	Phase I

Further Study Details: 

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.

PROTOCOL 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.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--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.

--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 prochlorperazine.

--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.

New York
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States

Study chairs or principal investigators

David R. Spriggs,  Study Chair,  Memorial Sloan-Kettering Cancer Center   

Study ID Numbers:  CDR0000067254; MSKCC-98116; NCI-G99-1572; MERCK-003-04
Record last reviewed:  September 2004
Last Updated:  October 13, 2004
Record first received:  December 10, 1999
ClinicalTrials.gov Identifier:  NCT00004057
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08