RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Folic acid may protect normal cells from the side effects of
chemotherapy and may increase the effectiveness of chemotherapy by making tumor cells more
sensitive to the drug. Lometrexol may stop the growth of tumors by blocking one of the
enzymes necessary for cancer cell growth. Combining chemotherapy with folic acid and
lometrexol may kill more tumor cells.
PURPOSE: Phase I trial to study the effectiveness of combining paclitaxel, folic acid, and
lometrexol in treating patients who have locally advanced or metastatic solid tumors.
- Determine the maximum tolerated dose and recommended phase II study dose of lometrexol
and paclitaxel when combined with folic acid in patients with locally advanced or
metastatic solid tumors.
- Determine the quantitative and qualitative toxic effects of this regimen in these
- Determine the plasma concentrations of lometrexol and paclitaxel and relate their
pharmacokinetics to toxicity outcome in these patients.
- Determine the antitumor activity of this regimen in these patients.
OUTLINE: This is a multicenter, dose-escalation study of lometrexol and paclitaxel.
Patients receive lometrexol IV over 30-60 seconds immediately followed by paclitaxel IV over
3 hours on day 1. Patients also receive oral folic acid beginning 7 days before
lometrexol/paclitaxel and continuing for 14 days. Treatment repeats every 21 days in the
absence of disease progression or unacceptable toxicity.
Doses of lometrexol and paclitaxel are escalated sequentially. Cohorts of 3-6 patients
receive escalating doses of lometrexol and paclitaxel until the maximum tolerated dose (MTD)
is determined. The MTD is defined as the dose at which at least 2 of 6 patients experience
dose-limiting toxicity. Six to twelve additional patients are treated at the recommended
phase II study dose (dose immediately preceding the MTD).
Patients are followed every 3 months.
PROJECTED ACCRUAL: Approximately 12-42 patients will be accrued for this study.
- Histologically or cytologically proven locally advanced or metastatic solid tumor
that is refractory to standard therapies or for which there are no therapies of
potential major benefit
- Measurable disease
- No hematologic malignancies, including leukemia, lymphoma, or multiple myeloma
- No symptomatic effusions or ascites unless drained before study entry
- No clinically apparent CNS metastases or carcinomatous meningitis
- 18 and over
- WHO 0-1
- At least 12 weeks
- Absolute neutrophil count at least 1,500/mm^3*
- Platelet count at least 100,000/mm^3*
- Hemoglobin at least 9.0 g/dL* NOTE: * Without growth factor support
- Bilirubin no greater than 2.0 mg/dL
- SGOT and SGPT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if
tumor involvement of liver)
- Albumin greater than 2.5 g/dL
- Glomerular filtration rate at least 65 mL/min
- No inflammatory bowel disease
- No radiation enteritis
- No malabsorption syndrome
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No known hypersensitivity to study drugs or related compounds (e.g., LY309887,
multi-targeted antifolate, AG-2034, methotrexate, docetaxel, or polyoxyethylated
- No active uncontrolled infection unless approved by the investigator
- No other severe concurrent disease that would preclude study therapy
- No body surface area greater than 3.0 m^2
- No known vitamin B12 deficiency
PRIOR CONCURRENT THERAPY:
- No concurrent routine or prophylactic filgrastim (G-CSF), sargramostim (GM-CSF), or
- No concurrent biologic-response modifiers
- At least 4 weeks since prior chemotherapy (6 weeks for mitomycin, carboplatin, or
nitrosourea) and recovered
- No other concurrent cytotoxic chemotherapy
- No concurrent hormonal therapy
- Recovered from prior radiotherapy
- No prior radiotherapy to 25% or more of bone marrow (e.g., whole-pelvic irradiation)
- No concurrent radiotherapy (including palliative radiotherapy)
- At least 4 weeks since prior major surgery and recovered
- At least 4 weeks since prior investigational agent
- No more than 2 prior therapies for locally advanced or metastatic solid tumor
- No other concurrent investigational agent
- No concurrent trimethoprim, co-trimoxazole, proguanil, or pyrimethamine