Safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of sorafenib and tanespimycin.
OBJECTIVE
Heat shock protein (Hsp) 90 inhibition affects the Raf kinase signaling pathway and could enhance antitumor effects of sorafenib, a Raf kinase inhibitor. The combination of sorafenib and tanespimycin [17-allyl-amino-geldanamycin (17-AAG); NSC 330507/KOS-953] was evaluated in a phase I trial with the primary objective of defining a phase II dose.


METHODS
The dose cohorts consisted of fixed continuous oral dosing of 400 mg sorafenib twice daily, starting at 14 days before tanespimycin, which was administered intravenously at escalating doses (starting at 300 mg/m,(2) with 50 mg/m(2) increments), on days 1, 8, and 15 in a 28-day cycle. Toxicity was assessed weekly, and response was evaluated every two cycles.


RESULTS
Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were renal cancer (12), melanoma (6), and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in one patient each were observed at 450 mg/m(2) of tanespimycin. One hundred fourteen cycles were administered with a median of four cycles (range 1-17 cycles). Plasma concentrations of sorafenib and metabolites reached steady state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients


CONCLUSIONS
Recommended phase II doses of this combination are 400 mg sorafenib twice daily and 400 mg/m(2) tanespimycin on days 1, 8, and 15, every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma.
Barbara Ann Karmanos Cancer Institute, Department of Medicine, Wayne State University, Detroit, Michigan 48201, USA. vaishamu@karmanos.org
Ulka N
UN
Vaishampayan
Angelika M
AM
Burger
Edward A
EA
Sausville
Lance K
LK
Heilbrun
Jing
J
Li
M Naomi
MN
Horiba
Merrill J
MJ
Egorin
Percy
P
Ivy
Simon
S
Pacey
Patricia M
PM
Lorusso
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077157:Sorafenib; D016019:Survival Analysis
D001557:Benzenesulfonates; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; C112765:tanespimycin; D000077157:Sorafenib