A Phase I Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Deforolimus in Patients with Advanced Malignancies

Abstract

Purpose This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Experimental Design Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities. Results Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P = 0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r = −0.38; P = 0.029). Conclusions Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.

First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014

“…The toxicity profile of AZD2014 had similarities with other TORC 1/2 inhibitors and more generally with allosteric m-TOR inhibitors and these were rash, mucositis, and fatigue (17,18,20,(22)(23)(24)(25). At 50-mg twice-daily continuous dosing AZD2014 was well tolerated.…”

Antitumor Activity of Ridaforolimus and Potential Cell-Cycle Determinants of Sensitivity in Sarcoma and Endometrial Cancer Models

“…Ridaforolimus was initially evaluated in 2 phase 1 clinical trials in patients with relapsed or refractory solid tumors (9,10). On the basis of preliminary evidence of clinical activity, as well as additional mechanistic considerations, endometrial cancer and sarcoma have emerged as promising indications for treatment with ridaforolimus.…”

Multimodality therapy for metastatic sarcomas confined to the lung

“…mTOR inhibitors have been studied in the metastatic sarcoma subpopulation. Ridaforolimus, a rapamycin analog, has been studied in sarcomas and may confer stability of disease while not having the adverse toxicities of combination chemotherapy (68)(69)(70)(71). The SUCCEED trial has studied this drug at multiple centers (72).…”