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A Pharmacokinetic Study Evaluating the Safety, Tolerability and Maximally Tolerated Dose of 7-Day Continuous Infusions of L-778,123 in Patients With Recurrent of Refractory Solid Malignancies

Phase 1
18 Years
Not Enrolling
Head and Neck Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Pharmacokinetic Study Evaluating the Safety, Tolerability and Maximally Tolerated Dose of 7-Day Continuous Infusions of L-778,123 in Patients With Recurrent of Refractory Solid Malignancies

OBJECTIVES: I. Determine the maximum tolerated dose of L-778,123 in patients with recurrent
or refractory solid tumors. II. Evaluate the safety and tolerability of L-778,123 including
qualitative, quantitative, and dose limiting toxicity in these patients. III. Assess the
pharmacokinetic profile of this regimen in these patients. IV. Evaluate the radiologic or
tumor marker responses to treatment in these patients. V. Evaluate the relationship between
ras mutations and response to treatment in these patients. VI. Determine the relationship
between plasma drug levels and farnesylation assay results.

OUTLINE: This is a dose escalation study. Patients receive continuous infusions of L-778,123
over 7 days every 3 weeks. Treatment continues in the absence of disease progression or
unacceptable toxic effects. All patients are observed for at least 1 week after the 7 day
infusion of L-778,123 prior to subsequent dose escalation. Cohorts of 3-6 patients receive
escalating doses of L-778,123 until the maximum tolerated dose (MTD) is reached. MTD is
defined as the dose at which no more than 2 of 6 patients experiences dose limiting
toxicities. Patients are followed until death.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Inclusion Criteria

DISEASE CHARACTERISTICS: Histologically proven recurrent or refractory solid tumors
including, but not limited to: Pancreatic cancer Bladder cancer Colon cancer Head and neck
cancer Lung cancer Measurable disease or a measurable tumor marker (not based solely on
cytopathological data) No primary or active metastatic CNS disease (assessed by edema or 2
radiologic imaging techniques at least 4 weeks apart)

PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-1 Life expectancy:
Greater than 3 months Hematopoietic: Absolute neutrophil count at least 1,500/mm3
Hemoglobin at least 9.0 g/dL Platelet count at least 100,000/mm3 PT or PTT no greater than
1.2 times upper limit of normal (ULN) Hepatic: Bilirubin no greater than 1.5 time ULN ALT
or AST no greater than 2 times ULN Alkaline phosphatase no greater than 2 times ULN Renal:
Creatinine no greater than 1.5 times ULN Cardiovascular: No grade 3 cardiac dysrhythmias
No atrial fibrillation No prior myocardial infarction No history of unstable angina No
history of congestive heart failure LVEF greater than 50% in patients with prior
cumulative anthracycline dose less than 450 mg/m2 of doxorubicin Other: HIV negative Not
pregnant or nursing Negative pregnancy test Fertile patients must use effective
double-barrier contraception for at least 2 weeks before, throughout, and at least 2 weeks
after the study Permanent central venous catheter in place No history of illicit drug or
alcohol abuse within the past 5 years No emotional or psychiatric disorders No known
significant drug allergies or serious adverse experiences with marketed or investigational
drugs No allergy to latex Normal serum electrolytes No other serious medical disorders No
active infections No history of significant retinal disorder or disease No history of
seizure disorders

PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 weeks since prior immunologic
therapy No concurrent immunologic therapy Chemotherapy: At least 4 weeks since prior
chemotherapy At least 6 weeks since prior mitomycin or nitrosoureas No prior high dose
chemotherapy with stem cell rescue No other concurrent chemotherapy No prior anthracycline
dose exceeding the equivalent of greater than 45O mg/m2 of doxorubicin Endocrine therapy:
At least 4 weeks since prior endocrine therapy (including steroids) No concurrent
endocrine therapy Radiotherapy: At least 4 weeks since prior radiotherapy No prior
radiation to greater than 25% of total bone marrow No concurrent radiotherapy Surgery: At
least 4 weeks since prior surgery No concurrent surgery Other: At least 30 days since
prior investigational agents No concurrent medications with dysrhythmic potential
including, but not limited to: terfenadine, astemizole, cisapride, diphenhydramine,
quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, tricyclic
antidepressants, haloperidol, risperidone, and indapamine No concurrent rifampin,
phenobarbital, phenytoin, or other inducers of CYP3A No concurrent triazolam, alprazolam,
midazolam, or other CYP3A metabolized benzodiazepines No concurrent HMG-CoA reductase
inhibitors (except fluvastatin) No concurrent anticoagulant therapy (low dose warfarin
therapy to maintain catheter patency allowed)

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

David R. Spriggs, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Federal Government

Study ID:




Start Date:

April 1998

Completion Date:

April 2000

Related Keywords:

  • Head and Neck Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • recurrent nasopharyngeal cancer
  • unspecified adult solid tumor, protocol specific
  • recurrent lip and oral cavity cancer
  • recurrent hypopharyngeal cancer
  • recurrent laryngeal cancer
  • recurrent paranasal sinus and nasal cavity cancer
  • recurrent oropharyngeal cancer
  • Head and Neck Neoplasms
  • Neoplasms



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