Talotrexin in Treating Patients With Advanced or Recurrent Solid Tumors

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of talotrexin in patients in patients with advanced
or recurrent solid tumors.

- Determine the safety of this drug in these patients.

- Determine the dose-limiting toxic effects of this drug in these patients.

Secondary

- Determine the pharmacokinetics of this drug in these patients.

- Correlate pharmacokinetic parameters of this drug or patient characteristics with
drug-related toxicity in these patients.

- Determine, preliminarily, the antitumor efficacy of this drug in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive talotrexin IV over 5 minutes on day 1 OR days 1 and 8 OR days 1, 8, and 15.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of talotrexin until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity. An additional 6-10 patients are treated at
the MTD.

Patients are followed at 1 month.

PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study within 9-12
months.

DISEASE CHARACTERISTICS:

- Diagnosis of malignant solid tumor

- Metastatic or inoperable disease

- No known curative or survival-prolonging palliative therapy exists OR failed these
prior therapies

- No leukemia

- No primary CNS tumor

- No third-space fluid collection (i.e., pleural effusion, ascites)

- Clinically insignificant small pleural or peritoneal effusions identified by CT
scan, MRI, or other diagnostic test allowed

- No active* brain metastases, including the following:

- Evidence of cerebral edema by CT scan or MRI

- Progression since prior imaging study

- Requirement for steroids

- Clinical symptoms of/from brain metastases NOTE: *Treated and/or stable brain
metastasis allowed provided patient is asymptomatic

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- At least 2 months

Hematopoietic

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- RBC folate ≥ lower limit of normal

Hepatic

- Bilirubin normal

- SGOT and SGPT ≤ 2.5 times upper limit of normal

Renal

- Creatinine clearance ≥ 50 mL/min

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No other uncontrolled serious medical or psychiatric illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

- No prior bone marrow transplantation

Chemotherapy

- More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

Endocrine therapy

- See Disease Characteristics

Radiotherapy

- More than 3 weeks since prior radiotherapy

- No concurrent radiotherapy

Surgery

- At least 3 weeks since prior surgery

Other

- Recovered from prior therapy

- More than 3 weeks since prior antifolate therapy