Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer

Cancer Chemother Pharmacol. 2011 Aug;68(2):547-52. doi: 10.1007/s00280-011-1620-1. Epub 2011 Apr 24.


Purpose: To assess further the tolerability and preliminary antitumor activity of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer.

Methods: This pilot study evaluated PD-0325901 on an intermittent dosing schedule. PD-0325901 was administered orally at 20 mg twice daily (BID) for 21 consecutive days followed by 7 days of no treatment. This dose was not well tolerated and consequently changed to 15 mg BID.

Results: Between October and December 2005, 13 patients with metastatic measurable disease were entered into the study (seven melanoma, three breast cancer, and three colon cancer). All patients had received prior systemic therapy and were treated with a total of 61 cycles of PD-0325901 (nine received an initial dose of 20 mg BID, four an initial dose of 15 mg BID). The study was terminated early because of an unexpected high incidence of musculoskeletal and neurological adverse events, including gait disturbance, memory impairment, confusion, mental status changes, mild to moderate visual disturbances, and muscular weakness including neck weakness ("dropped-head syndrome"). Other common toxicities were diarrhea, acneiform rash, fatigue, and nausea. There was no significant hematologic toxicity, and chemistry abnormalities were rare. One patient achieved a confirmed complete response, and five patients had stable disease.

Conclusions: PD-0325901 can cause significant musculoskeletal, neurological, and ocular toxicity at doses ≥ 15 mg BID. Future studies with adaptive designs might evaluate doses ≤ 10 mg BID in tumor types with a high incidence of Ras and Raf mutations. ClinicalTrials.gov identifier NCT00147550.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects*
  • Benzamides / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Cohort Studies
  • Colonic Neoplasms / drug therapy*
  • Diphenylamine / administration & dosage
  • Diphenylamine / adverse effects
  • Diphenylamine / analogs & derivatives*
  • Diphenylamine / therapeutic use
  • Early Termination of Clinical Trials
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Eye Diseases / chemically induced
  • Female
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Middle Aged
  • Musculoskeletal Diseases / chemically induced
  • Neoplasm Staging
  • Neurotoxicity Syndromes
  • Pilot Projects


  • Antineoplastic Agents
  • Benzamides
  • PD 0325901
  • Diphenylamine
  • Extracellular Signal-Regulated MAP Kinases

Associated data

  • ClinicalTrials.gov/NCT00147550