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A Phase I and Pharmacokinetic Study Evaluating the Safety, Tolerability, and Maximally Tolerated Dose of Combination Therapy With Paclitaxel and L-778,123 in Patients With Recurrent or Refractory Solid Malignancies


Phase 1
18 Years
N/A
Not Enrolling
Both
Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I and Pharmacokinetic Study Evaluating the Safety, Tolerability, and Maximally Tolerated Dose of Combination Therapy With Paclitaxel and L-778,123 in Patients With Recurrent or Refractory Solid Malignancies


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.

Inclusion 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

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
prochlorperazine

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

David R. Spriggs, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Federal Government

Study ID:

98-116

NCT ID:

NCT00004057

Start Date:

December 1998

Completion Date:

December 2000

Related Keywords:

  • Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • recurrent adult Hodgkin lymphoma
  • unspecified adult solid tumor, protocol specific
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent adult Burkitt lymphoma
  • recurrent adult T-cell leukemia/lymphoma
  • recurrent mantle cell lymphoma
  • angioimmunoblastic T-cell lymphoma
  • anaplastic large cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • Lymphoma

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021