Phase III Trial of Gemcitabine, Curcumin and Celebrex in Patients With Advance or Inoperable Pancreatic Cancer

Pancreatic cancer is an aggressive disease with an extremely poor prognosis. It is the forth leading cause of cancer-related fatalities, with an estimated one-year and five-year survival rate of 21% and 5%, respectively. Despite recent progress, the median survival time is 6-10 months for patients with locally advanced disease and 3-6 months for metastatic disease (1). The anti-metabolite gemcitabine has become the standard chemotherapy for locally advanced and metastatic pancreatic cancer, after demonstrating an improved rate of clinical benefit response and an overall survival advantage over 5-FU (2). In addition to its clinical effectiveness gemcitabine has a manageable toxicity profile, making it an attractive agent to investigate in combination with newer agents. Series of phase III trials were conducted examining the efficacy of the combination of gemcitabine and a second cytotoxic agent, including 5-FU, cisplatin, oxaliplatin and irinotecan. These gemcitabine doublets demonstrated no survival advantage over single-agent gemcitabine (3-6). However, the rationale for continuing to study gemcitabine-based combinations remains compelling.

Curcumin (diferuloylmethane) is a natural compound derived from the rhizome of Curcuma Longa, an East Indian plant, commonly called turmeric. It has been shown to possess potent anti-inflammatory and anti-oxidative properties, for which it has a long history of dietary use as a food additive. Curcumin has also a potent anti-proliferative effects against a variety of cancer cell lines in vitro, which stem from its ability to modulate many intracellular signal transduction pathways (7). Human phase I-II studies found curcumin to be safe, and indicated no dose-limiting toxicity when taken by mouth at doses up to 10 g/day (8, 9). This data, together with the dismal therapeutic options available for pancreatic cancer patients, suggest that curcumin warrants investigation in this setting. Investigators from MD Anderson Cancer Center and Rambam Medical Center in Haifa, have recently initiated, separately, a phase II study of single agent Curcumin in patients with pancreatic cancer (10).

One of the lessons learned from cancer research in recent decades is that combination strategies can provide dramatic improvement in a therapy's safety and efficacy over mono-therapeutic regiments, especially if the combined drugs differ in their mode of action. In a recent paper that was accepted for publication we demonstrated, in vitro, the mechanism, clinical importance and implications of a novel combinatorial therapy, of celecoxib and curcumin, that was discovered in our lab, in inhibiting the growth of several pancreatic cell lines. P-34 (expressing high levels of COX -2), MiaPaca (Expressing low levels of COX-2) and Panc-1 (no expression of COX -2) cell lines were exposed to different concentrations of celecoxib (0-40µM), curcumin (0-20µM) and their combination. In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis.

These experiments further demonstrate, for the first time, that the combination effect is correlated with synergistic augmentation of apoptosis and involves down-regulation of COX-2 protein.

The present study evaluates gemcitabine in combination with curcumin and celecoxib for patients with pancreatic cancer.

Study Overview

• Status: Unknown
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: Gemcitabine; Drug: Curcumin; Drug: Celebrex

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Tel Aviv, Israel, 64239
    • Recruiting
    • Sourasky Medical Center
    • Contact: Nadir Arber, M.D, MSc, MHA; Phone Number: 03-6953179; Email: nadir@tasmc.health.gov.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Locally advanced or metastatic adenocarcinoma of the pancreas, confirmed by histology or cytology.
• No prior chemotherapy for pancreatic cancer.
• Performance status 0-2 (ECOG scale).
• Age ≥ 18 y.
• Adequate hematologic function (ANC ≥ 1500/mm³, platelet count ≥ 100,000/mm³).
• Adequate hepatic function (total bilirubin ≤ 2.0xUNL and AST, ALT and AP ≤ 5.0xUNL)
• Adequate renal function (creatinine ≤ 2.0).
• Signed informed consent.

Exclusion Criteria:

• A history of treated or active central nervous system involvement by the tumor or active neurological disease.
• Prior radiation. Patients with disease outside the irradiation field or documented disease progression of previously irradiated disease are eligible.
• Unstable medical condition, including uncontrolled diabetes mellitus or hypertension, active infection, unstable CHF, uncontrolled arrhythmias or unstable coagulation disorders.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Collaborators and Investigators

• Sponsor: Tel-Aviv Sourasky Medical Center
• Investigators: Principal Investigator: Arber Nadir, M.D, Msc, MHA, University of Tel Aviv

Study record dates

Study Major Dates

• Study Start: June 1, 2005

Study Registration Dates

• First Submitted: June 13, 2007
• First Submitted That Met QC Criteria: June 13, 2007
• First Posted (Estimate): June 14, 2007

Study Record Updates

• Last Update Posted (Estimate): June 14, 2007
• Last Update Submitted That Met QC Criteria: June 13, 2007
• Last Verified: June 1, 2007

More Information

Terms related to this study

• Keywords: pancreas; Locally advanced or metastatic adenocarcinoma of the; confirmed by histology or cytology; Inoperatable
• 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; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cyclooxygenase 2 Inhibitors; Gemcitabine; Celecoxib; Curcumin
• Other Study ID Numbers: TASMC-07-NA-132-CTIL