A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer.
OBJECTIVE
Preclinical data have demonstrated that farnesyltransferaseinhibitors (FTIs) are radiation sensitizers in selected cell lines. The objective of this Phase I trial was to determine the maximally tolerated dose of the FTI L-778,123 in combination with radiotherapy in non-small cell lung cancer (NSCLC) and head and neck cancer (HNC).


METHODS
L-778,123 was given by continuous i.v. infusion and dose escalated in conjunction with standard radiotherapy. The presence of a ras mutation was not required for study entry.


RESULTS
Nine patients (six NSCLC patients and three HNC patients) were enrolled on two dose levels of FTI. No dose-limiting toxicities were observed at the first dose level of 280 mg/m2/day during weeks 1, 2, 4, and 5 of radiotherapy. One episode of dose-limiting toxicity, grade IV neutropenia, was observed in one of three patients treated at 560 mg/m2/day during weeks 1, 2, 4, 5, and 7. No episodes of dose-limiting mucositis, esophagitis, or pneumonitis were observed. Of the four patients with NSCLC with evaluable disease, three patients had a complete response to treatment and one patient had a partial response. A complete clinical response to treatment was observed in two patients with HNC. In vitro studies in tumor cells obtained from a NSCLC patient on this trial showed radiosensitization with FTI and that tumor cells accumulated in G2-M after L-778,123 treatment.


CONCLUSIONS
The combination of L-778,123 and radiotherapy at dose level 1 is associated with acceptable toxicity. Local responses have been observed in four NSCLC patients without a clear increase in radiotherapy-associated toxicities.
Hahn
Stephen M
SM
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. hahn@xrt.upenn.edu
Bernhard
Eric J
EJ
Regine
William
W
Mohiuddin
Mohammed
M
Haller
Daniel G
DG
Stevenson
James P
JP
Smith
Debbie
D
Pramanik
Barnali
B
Tepper
Joel
J
DeLaney
Thomas F
TF
Kiel
Krystina D
KD
Morrison
Briggs
B
Deutsch
Paul
P
Muschel
Ruth J
RJ
McKenna
W Gillies
WG
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy / Q000009:adverse effects; D004307:Dose-Response Relationship, Radiation; D051231:Farnesyltranstransferase; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D009325:Nausea / Q000139:chemically induced; D012871:Skin Diseases / Q000139:chemically induced; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014839:Vomiting / Q000139:chemically induced
D007093:Imidazoles; C425231:L 778,123; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase