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

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

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

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer; Stage II Pancreatic Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: gemcitabine hydrochloride; Drug: 7-hydroxystaurosporine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (UCN-01, gemcitabine hydrochloride); 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.

Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; gemcitabine; dFdC; difluorodeoxycytidine hydrochloride; Drug: 7-hydroxystaurosporine; Given IV; Other Names: UCN-01

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Linus Ho, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): May 1, 2006

Study Registration Dates

• First Submitted: June 6, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): January 23, 2013
• Last Update Submitted That Met QC Criteria: January 22, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; 7-hydroxystaurosporine
• Other Study ID Numbers: NCI-2012-02468; U01CA062461 (U.S. NIH Grant/Contract); DM01-553; CDR0000069380 (Registry Identifier: PDQ (Physician Data Query))