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A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms

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Abstract

Purpose

To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations.

Methods

Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1–2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine “maintenance” doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22–27. The pharmacokinetics of perifosine with these schedules was characterized.

Results

Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days.

Conclusions

Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.

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Acknowledgments

We thank the nursing staff of National Cancer Institute and the fellows of the Medical Oncology Branch at National Cancer Institute for their care of our patients; Cancer Therapy and Evaluation Program for sponsoring the trial; Eunhee W. Woo (deceased, and to whose memory we dedicate this paper), Suoping Zhai, Kyung Hwang and Nicola Smith for their assistance in conducting this study; and Victoria Giffi for editorial assistance. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. This is a US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government.

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Author notes

  1. Edward A. Sausville

    Present address: Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA

Authors and Affiliations

  1. Medical Oncology Branch, National Cancer Institute, Bldg 10/Room 5A01, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    William D. Figg, Manish Monga, Donna Headlee, Avni Shah, Cindy H. Chau, Cody Peer, Yusri A. Elsayed, Qin C. Ryan & Mikhail Kalnitskiy

  2. Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD, USA

    Richard Messman, Melinda Hollingshead & Edward A. Sausville

  3. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Anthony J. Murgo & Susan G. Arbuck

  4. National Institute for Dental and Craniofacial Research, Bethesda, MD, 20892, USA

    Adrian M. Senderowicz

  5. Science Applications International Corp., Frederick, MD, USA

    Giovanni Melillo

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  1. William D. Figg
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Correspondence to William D. Figg.

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Figg, W.D., Monga, M., Headlee, D. et al. A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms. Cancer Chemother Pharmacol 74, 955–967 (2014). https://doi.org/10.1007/s00280-014-2569-7

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