Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC).

Abstract

PURPOSE:

Recent data indicate that there is a significant cross-talk between the PI3K/Akt/mTOR and androgen receptor signaling pathways. We evaluated safety and tolerability as well as potential drug-drug interaction of ridaforolimus, a mammalian target of rapamycin (mTOR) inhibitor, when combined with the androgen receptor inhibitor bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer.

PATIENTS AND METHODS:

Patients were treated with the combination of ridaforolimus 30 mg/day for 5 consecutive days each week and bicalutamide 50 mg/day. Ridaforolimus pharmacokinetics was assessed with and without bicalutamide.

RESULTS:

Twelve patients were enrolled including 1 screen failure. Dose reductions were required in 7 patients. Three of the 11 patients experienced a dose-limited toxicity, 1 with Grade 3 hyperglycemia and 2 with Grade 2 stomatitis leading to <75 % of planned ridaforolimus dose during the first 35 days of study treatment. The pharmacokinetic results showed no differences in exposures to ridaforolimus with and without concomitant bicalutamide administration.

CONCLUSIONS:

Although there was no evidence of a clinically relevant pharmacological drug-drug interaction, the occurrence of dose-limiting toxicities in 3 of 11 evaluable patients at a reduced dose of ridaforolimus of 30 mg/day suggests that this combination may not be well suited for asymptomatic or minimally symptomatic prostate cancer patients.

• Authors: Hielke J Meulenbeld, Johann S de Bono, Scott T Tagawa, Young E Whang, Xiaoyun Li, Karl H Heath, Anthe S Zandvliet, Scot W Ebbinghaus, Gary R Hudes, Ronald de Wit
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 72 Issue 4 Pg. 909-16 (Oct 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23921574 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Antagonists
• Anilides
• Nitriles
• Tosyl Compounds
• ridaforolimus
• bicalutamide
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Aged
• Androgen Antagonists (adverse effects, pharmacokinetics, therapeutic use)
• Anilides (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Interactions
• Follow-Up Studies
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Nitriles (administration & dosage)
• Orchiectomy
• Prospective Studies
• Prostatic Neoplasms (drug therapy, pathology)
• Sirolimus (administration & dosage, analogs & derivatives)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Tosyl Compounds (administration & dosage)