UCN-01 and Irinotecan in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

• Determine the maximum tolerated dose and recommended phase II dose of UCN-01 and irinotecan in patients with advanced solid tumors, primarily lung, ovarian, and gastrointestinal tumors.
• Determine the acute and chronic toxicity profile of this regimen in these patients.
• Determine the pharmacokinetics of this regimen in these patients.
• Determine, preliminarily, the anti-tumor effect of this regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive UCN-01 IV over 3 hours on day 1 and irinotecan IV over 90 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of UCN-01 and irinotecan 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. At least 6 patients are treated at the recommended phase II dose.

Patients are followed at 1 month.

PROJECTED ACCRUAL: Approximately 20-30 patients will be accrued for this study within 7-15 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative therapy does not exist or is no longer effective

• Gastrointestinal, lung, and ovarian malignancies are given priority
• No brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 3 months

Hematopoietic

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin normal
• AST/ALT no greater than 2.5 times upper limit of normal (ULN)

Renal

• Creatinine normal OR
• Creatinine clearance at least 60 mL/min

Cardiovascular

• No symptomatic coronary artery disease
• No symptomatic cardiac dysfunction
• No symptoms suggestive of coronary artery disease
• LVEF at least 50%

Pulmonary

• No symptomatic pulmonary dysfunction
• FEV_1 greater than 75% of predicted
• DLCO greater than 75% of predicted

Other

• Amylase no greater than 2 times ULN
• No other concurrent uncontrolled illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No diabetes mellitus or random glucose more than 200 mg/dL
• No prior allergic reaction attributed to compounds of similar biological or chemical composition to UCN-01 or irinotecan (including rash and systemic allergic reaction causing hypotension and respiratory distress)
• No chronic diarrhea (more than 5 stools/day)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 14 days before, during, and for at least 30 days after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• Prior UCN-01 and irinotecan allowed

Endocrine therapy

• Not specified

Radiotherapy

• At least 4 weeks since prior radiotherapy and recovered
• No prior mediastinal radiation

Surgery

• Not specified

Other

• At least 14 days since prior warfarin
• No concurrent warfarin unless required for maintaining patency of existing, permanent IV catheters
• No concurrent commercial or other investigational anticancer agents or therapies
• No concurrent combination antiretroviral therapy for HIV-positive patients