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

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Abstract

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.

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Acknowledgments

We would like to thank all of the participating patients and their families, as well as the network of investigators, research nurses, study coordinators, and operations staff. Medical writing assistance was provided by Christine Arris of ACUMED® (Tytherington, UK), and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc.

Conflicts of interest

PDB’s institution (The Angeles Clinic) received research funding from Pfizer for the trial itself. GAD has nothing to disclose. DB’s institution (Sharp Clinical Oncology Research) receives research funding from Pfizer for participating in the trial. CHR received research funding from Pfizer for the trial itself, and his institution (Sharp Clinical Oncology Research) has received a commercial research grant from Merck for a clinical trial. CRG has performed a consultant/advisory role for Pfizer. ADR is an employee of Pfizer and owns stock in Pfizer.

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Author notes

  1. Chris R. Garrett

    Present address: Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

Authors and Affiliations

  1. The Angeles Clinic and Research Institute, 2001 Santa Monica Boulevard, Suite 560 W, Santa Monica, CA, 90404-2104, USA

    Peter D. Boasberg

  2. Sharp Clinical Oncology Research, 3075 Health Center Drive # 102, San Diego, CA, 92123, USA

    Charles H. Redfern & David Bodkin

  3. Moores Cancer Center, University of California at San Diego, 3855 Health Sciences Drive, La Jolla, San Diego, CA, 92093, USA

    Gregory A. Daniels

  4. Moffitt Cancer Center, University of South Florida, Tampa, FL, USA

    Chris R. Garrett

  5. Pfizer Oncology, San Diego, CA, USA

    Alejandro D. Ricart

Authors
  1. Peter D. Boasberg
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  2. Charles H. Redfern
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  4. David Bodkin
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Corresponding author

Correspondence to Peter D. Boasberg.

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Boasberg, P.D., Redfern, C.H., Daniels, G.A. et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol 68, 547–552 (2011). https://doi.org/10.1007/s00280-011-1620-1

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  • DOI: https://doi.org/10.1007/s00280-011-1620-1

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