Paclitaxel, Folic Acid, and Lometrexol in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: 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 patients. 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.

Official Title
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A Phase I Trial of Lometrexol Sodium and Paclitaxel Adminsitered Intravenously Every 21 Days in Conjunction With Oral Folic Acid in Patients With Solid Tumors

Conditions
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Drug/Agent Toxicity by Tissue/Organ, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Dietary Supplement: folic acid
* Drug: lometrexol
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: 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 PATIENT CHARACTERISTICS: Age: 18 and over Performance status: WHO 0-1 Life expectancy: At least 12 weeks Hematopoietic: 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 Hepatic: 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 Renal: Glomerular filtration rate at least 65 mL/min Gastrointestinal: No inflammatory bowel disease No radiation enteritis No malabsorption syndrome Other: 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 castor oil) 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: Biologic therapy: No concurrent routine or prophylactic filgrastim (G-CSF), sargramostim (GM-CSF), or epoetin alfa No concurrent biologic-response modifiers Chemotherapy: At least 4 weeks since prior chemotherapy (6 weeks for mitomycin, carboplatin, or nitrosourea) and recovered No other concurrent cytotoxic chemotherapy Endocrine therapy: No concurrent hormonal therapy Radiotherapy: 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) Surgery: At least 4 weeks since prior major surgery and recovered Other: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Dietary Supplement: folic acid|nan|
|Drug: lometrexol|nan|
|Drug: paclitaxel|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific, drug/agent toxicity by tissue/organ