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PURPOSE: 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). EXPERIMENTAL DESIGN: 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.

Type

Journal article

Journal

Clin Cancer Res

Publication Date

05/2002

Volume

8

Pages

1065 - 1072

Keywords

Adult, Aged, Alkyl and Aryl Transferases, Carcinoma, Non-Small-Cell Lung, Cell Survival, Combined Modality Therapy, Dose-Response Relationship, Radiation, Farnesyltranstransferase, Female, Head and Neck Neoplasms, Hematologic Diseases, Humans, Imidazoles, Lung Neoplasms, Male, Middle Aged, Mouth Mucosa, Nausea, Skin Diseases, Stomatitis, Treatment Outcome, Tumor Cells, Cultured, Vomiting