Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.

PURPOSE R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2. RESULTS No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15. CONCLUSION Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

• Publication year

  2003

• Venue

  Journal of Clinical Oncology

• Publication date

  2003-04-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1200/JCO.2003.08.040PMID 12663718
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Single-agent R115777 did not show antitumor activity in previously untreated metastatic pancreatic cancer.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• No objective responses were observed, with median time to progression of 4.9 weeks and median survival of 19.7 weeks in the treated metastatic pancreatic adenocarcinoma cohort.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• R115777 produced partial inhibition of FTase activity in peripheral-blood mononuclear cells and reduced HDJ-2 farnesylation during treatment.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review

• farnesyltransferase

  enzyme

  The enzyme targeted for posttranslational protein farnesylation and monitored here through its activity in blood mononuclear cells.

  Aliases: FTase

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• hdj-2 farnesylation

  biomarker, protein modification

  The farnesylation status of the chaperone protein HDJ-2, assessed by western blot as a pharmacodynamic marker.

  Aliases: HDJ-2

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• metastatic pancreatic adenocarcinoma

  cancer type, patient population

  The advanced pancreatic cancer population enrolled for initial treatment with measurable metastatic disease.

  Aliases: metastatic pancreatic cancer

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• objective response

  outcome, endpoint

  A clinical tumor-response endpoint indicating a measurable reduction in disease burden.

  Aliases: objective responses

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• overall survival

  outcome, endpoint

  The interval from treatment start until death from any cause.

  Aliases: survival time, median survival

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• peripheral-blood mononuclear cells

  cell population, sample

  Circulating blood mononuclear cells used as the pharmacodynamic source for measuring FTase activity.

  Aliases: PBMCs

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• r115777

  drug, inhibitor

  A selective nonpeptidomimetic farnesyltransferase inhibitor administered orally in this metastatic pancreatic cancer trial.

  Aliases: farnesyltransferase inhibitor R115777

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• single-agent antitumor activity

  therapeutic effect, outcome

  The ability of R115777 given alone to produce clinically meaningful tumor control in the treated patients.

  Aliases: single-agent activity

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review
• time to progression

  outcome, endpoint

  The interval from treatment start until documented disease progression.

  Aliases: TTP

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (n259mg7uxy) reviewq (76h6bfydm6) review

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  2012cites this paper
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  2009cites this paper
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• Biologic therapies for advanced pancreatic cancer

  2008cites this paper
• Challenges in developing targeted therapy for pancreatic adenocarcinoma

  2008cites this paper
• Pancreatic cancer: from molecular signature to target therapy.

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