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Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

Monica M. Mita, Alain C. Mita, Quincy S. Chu, Eric K. Rowinsky, Gerald J. Fetterly, Michelle Goldston, Amita Patnaik, Lesley Mathews, Alejandro D. Ricart, Theresa Mays, Heather Knowles, Victor M. Rivera, Jeff Kreisberg, Camille L. Bedrosian, Anthony W. Tolcher

From the Cancer Therapy and Research Center, Institute for Drug Development; The University of Texas Health Science Center, San Antonio, TX; Cognigen Corp, Buffalo, NY; and ARIAD Pharmaceuticals Inc, Cambridge MA

Corresponding author: Anthony W. Tolcher, MD, FRCPC, South Texas Accelerated Research Therapeutics, 4319 Medical Drive, Suite 205, San Antonio, TX 78229; e-mail: atolcher{at}start.stoh.com

Purpose This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies.

Patients and Methods Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed.

Results Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions.

Conclusion The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

Supported by ARIAD Pharmaceuticals Inc, Cambridge, MA.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA, and at the 16th European Organisation for Research and Treatment of Cancer/National Cancer Institute/American Association for Cancer Research International Conference on Molecular Targets and Cancer Therapeutics, September 28–October 1, 2004, Geneva, Switzerland.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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