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

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of combining UCN-01 with gemcitabine in treating patients who have unresectable or metastatic pancreatic cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. UCN-01 may help gemcitabine kill more cancer cells by making tumor cells more sensitive to the drug

Detailed Description
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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.

Official Title
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A Phase I Study Of UCN-01 In Combination With Gemcitabine In Unresectable Or Metastatic Pancreatic Carcinoma

Conditions
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Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage II Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
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* Drug: 7-hydroxystaurosporine
* Drug: gemcitabine hydrochloride
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (UCN-01, gemcitabine hydrochloride)<br>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. | Drug: 7-hydroxystaurosporine<br>* Given IV<br>* Other names: UCN-01;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity |  | Up to 4 years | 
| Pharmacokinetic profiles |  | Weeks 1-6 for UCN-01 and weeks 1 and 4 for intracellular gemcitabine | 
| Recommended phase II doses |  | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency, extent, and duration of any tumor responses |  | Up to 4 years |