Skip to main content

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

Publication ,  Journal Article
Cohen, SJ; Ho, L; Ranganathan, S; Abbruzzese, JL; Alpaugh, RK; Beard, M; Lewis, NL; McLaughlin, S; Rogatko, A; Perez-Ruixo, JJ; Thistle, AM ...
Published in: J Clin Oncol
April 1, 2003

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Clin Oncol

DOI

ISSN

0732-183X

Publication Date

April 1, 2003

Volume

21

Issue

7

Start / End Page

1301 / 1306

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Quinolones
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Middle Aged
  • Male
  • Humans
  • Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Cohen, S. J., Ho, L., Ranganathan, S., Abbruzzese, J. L., Alpaugh, R. K., Beard, M., … Meropol, N. J. (2003). Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol, 21(7), 1301–1306. https://doi.org/10.1200/JCO.2003.08.040
Cohen, Steven J., Linus Ho, Sulabha Ranganathan, James L. Abbruzzese, R Katherine Alpaugh, Mary Beard, Nancy L. Lewis, et al. “Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.J Clin Oncol 21, no. 7 (April 1, 2003): 1301–6. https://doi.org/10.1200/JCO.2003.08.040.
Cohen SJ, Ho L, Ranganathan S, Abbruzzese JL, Alpaugh RK, Beard M, et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol. 2003 Apr 1;21(7):1301–6.
Cohen, Steven J., et al. “Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.J Clin Oncol, vol. 21, no. 7, Apr. 2003, pp. 1301–06. Pubmed, doi:10.1200/JCO.2003.08.040.
Cohen SJ, Ho L, Ranganathan S, Abbruzzese JL, Alpaugh RK, Beard M, Lewis NL, McLaughlin S, Rogatko A, Perez-Ruixo JJ, Thistle AM, Verhaeghe T, Wang H, Weiner LM, Wright JJ, Hudes GR, Meropol NJ. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol. 2003 Apr 1;21(7):1301–1306.

Published In

J Clin Oncol

DOI

ISSN

0732-183X

Publication Date

April 1, 2003

Volume

21

Issue

7

Start / End Page

1301 / 1306

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Quinolones
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Middle Aged
  • Male
  • Humans
  • Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins