A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity.
Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.
Adjei
A A
AA
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. adjei.alex@mayo.edu
Erlichman
C
C
Davis
J N
JN
Cutler
D L
DL
Sloan
J A
JA
Marks
R S
RS
Hanson
L J
LJ
Svingen
P A
PA
Atherton
P
P
Bishop
W R
WR
Kirschmeier
P
P
Kaufmann
S H
SH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D034904:Lamin Type A; D034882:Lamins; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000032:analysis; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects*; D011498:Protein Precursors / Q000032:analysis; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins; D010880:Piperidines; D011498:Protein Precursors; D011725:Pyridines; C090764:prelamin A; C115354:lonafarnib; D003986:Dibenzocycloheptenes