RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Combining more than one drug may kill more tumor cells.
PURPOSE: Phase I trial to study the effectiveness of irinotecan plus raltitrexed in treating
patients who have refractory solid tumors that have not responded to previous therapy.
OBJECTIVES: I. Determine the maximum tolerated dose of irinotecan in combination with
raltitrexed in patients with refractory solid tumors. II. Describe and quantify the toxic
effects of this combination treatment regimen in a minimally pretreated patient population.
III. Determine the pharmacokinetics of this combination treatment regimen. IV. Document any
antitumor activity of this combination treatment regimen in this patient population.
OUTLINE: This is a dose escalation study of irinotecan and raltitrexed. Patients receive
irinotecan IV over 90 minutes on days 1 and 8 followed by raltitrexed IV over 15 minutes on
day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable
toxicity. Cohorts of 3-6 patients each receive escalating doses of irinotecan and
raltitrexed until the maximum tolerated dose (MTD) is determined. The MTD is defined as the
dose preceding that at which 2 of 6 patients experience dose limiting toxicities. Additional
cohorts receive raltitrexed on day 2 rather than day 1 near the final dose levels of the
PROJECTED ACCRUAL: A maximum of 36 patients will be accrued for this study within 1 year.
DISEASE CHARACTERISTICS: Histologically proven malignant solid tumor that has failed prior
conventional chemotherapy or for which no established therapy exists Recurrent or
metastatic gastrointestinal adenocarcinoma with no prior therapy eligible No evidence of
CNS metastases (brain or leptomeningeal disease)
PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-1 Life expectancy: At
least 12 weeks Hematopoietic: WBC at least 3,500/mm3 Neutrophil count at least 1,500/mm3
Platelet count at least 100,000/mm3 Hepatic: Bilirubin no greater than 1.8 mg/dL SGOT and
SGPT less than 3 times upper limit of normal (ULN) Alkaline phosphatase less than 3 times
ULN (5 times ULN for metastatic disease) Renal: Creatinine no greater than 1.8 mg/dL OR
Creatinine clearance at least 60 mL/min Cardiovascular: No congestive heart failure Other:
No uncontrolled diabetes Not pregnant or nursing Negative pregnancy test No other serious
medical illness (e.g. clinically active infectious process) No psychiatric illness
precluding study No ascites or pleural effusion
PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: At least 4 weeks
since prior chemotherapy and recovered No more than 1 prior adjuvant chemotherapy regimen
No more than 1 prior chemotherapy regimen for recurrent or metastatic disease No prior
irinotecan or raltitrexed At least 8 weeks since prior nitrosourea or mitomycin and
recovered Endocrine therapy: Not specified Radiotherapy: At least 4 weeks since prior
radiotherapy and recovered Prior radiotherapy limited to no greater than 25% of bone
marrow Surgery: Not specified