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


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.
Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3008 AE, Rotterdam, The Netherlands, hielkem@hotmail.com.
Hielke J
HJ
Meulenbeld
Johann S
JS
de Bono
Scott T
ST
Tagawa
Young E
YE
Whang
Xiaoyun
X
Li
Karl H
KH
Heath
Anthe S
AS
Zandvliet
Scot W
SW
Ebbinghaus
Gary R
GR
Hudes
Ronald
R
de Wit
D000368:Aged; D000726:Androgen Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000008:administration & dosage; D009919:Orchiectomy; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014105:Tosyl Compounds / Q000008:administration & dosage
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C515074:ridaforolimus; C053541:bicalutamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus