UCN-01 and Gemcitabine in Treating Patients With Unresectable or Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To determine the safety and toxicity profile of UCN-01 when given in combination with gemcitabine to patients with unresectable or metastatic adenocarcinoma of the pancreas.

II. To characterize the pharmacokinetic profiles of gemcitabine and UCN-01 when given in combination and to correlate various measurements of UCN-01 with intracellular concentrations.

III. To determine recommended doses of UCN-01 and gemcitabine in combination to be used in a planned subsequent phase II trial.

SECONDARY OBJECTIVES:

I. To record the frequency, extent, and duration of any tumor responses. II. To correlate serum alpha-1 acid glycoprotein (AGP) levels with UCN-01 pharmacokinetics and toxicity.

OUTLINE: This is a dose-escalation study.

Patients receive gemcitabine IV over 1-2 hours on days 1 and 8 followed by UCN-01 IV over 3 hours on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Sequential dose escalation of UCN-01 is followed by sequential dose escalation of gemcitabine.

Cohorts of 3-6 patients receive escalating doses of UCN-01 and then gemcitabine until the maximum tolerated dose (MTD) of the combination is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, at least 6 patients are treated at the recommended phase II dose.

Inclusion criteria

• Histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the pancreas
• Unidimensionally measurable disease

• At least 20 mm by conventional techniques
• At least 10 mm by spiral CT scan
• Tumor lesions in a previously irradiated area are not considered measurable
• No known brain metastases

• Patients with signs or symptoms of CNS metastasis at any time during screening must have a negative CT scan or MRI of the brain
• Performance status - ECOG 0-2
• Performance status - Karnofsky 60-100%
• More than 3 months
• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count greater than 100,000/mm^3
• Bilirubin no greater than 1.5 mg/dL
• ALT and AST no greater than 2.5 times upper limit of normal
• Creatinine normal
• Creatinine clearance at least 60 mL/min
• No prior coronary artery disease
• No symptomatic cardiac dysfunction
• No prior myocardial infarction
• No active angina (even if controlled by medication)
• No positive stress test
• No uncontrolled arrhythmia
• Left ventricular ejection fraction at least 45%
• Patients with symptoms suggestive of coronary artery disease or arrhythmia must have no evidence of cardiac pathology
• No symptomatic pulmonary dysfunction
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No prior allergic reactions attributed to compounds of similar chemical or biological composition to UCN-01 or other study agents
• No insulin-dependent diabetes mellitus
• No other concurrent uncontrolled illness
• No ongoing or active infections
• No concurrent psychiatric illness
• No other active malignancy
• No other solid tumor within the past 5 years except neoplasia in situ or nonmelanomatous skin cancer
• No social situations that would preclude study compliance
• No concurrent over-the-counter biologics
• No concurrent growth factors during the first study course
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No more than 2 prior chemotherapy regimens (e.g., gemcitabine and/or experimental agents) alone or in combination with radiotherapy as neoadjuvant or adjuvant therapy for resectable, unresectable, or metastatic disease
• See Chemotherapy
• At least 6 weeks since prior radiotherapy and recovered
• Prior radiotherapy directed only at the primary tumor bed allowed
• No prior radiotherapy to the mediastinum, pelvis, lower spine, or more than 20% of bone marrow
• At least 4 weeks since prior major surgery
• At least 4 weeks since prior investigational agents
• Concurrent enrollment in non-therapy trials (e.g., quality of life) allowed
• No concurrent herbal remedies
• No concurrent treatment for another active malignancy
• No concurrent warfarin for anticoagulation
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational or commercial anticancer agents or therapies