A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer.

Abstract

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.

• Authors: Stephen M Hahn, Eric J Bernhard, William Regine, Mohammed Mohiuddin, Daniel G Haller, James P Stevenson, Debbie Smith, Barnali Pramanik, Joel Tepper, Thomas F DeLaney, Krystina D Kiel, Briggs Morrison, Paul Deutsch, Ruth J Muschel, W Gillies McKenna
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 5 Pg. 1065-72 (May 2002) ISSN: 1078-0432 [Print] United States
• PMID: 12006520 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• L 778,123
• Alkyl and Aryl Transferases
• Farnesyltranstransferase

Topics

• Adult
• Aged
• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology, radiotherapy)
• Cell Survival (drug effects, radiation effects)
• Combined Modality Therapy (adverse effects)
• Dose-Response Relationship, Radiation
• Farnesyltranstransferase
• Female
• Head and Neck Neoplasms (drug therapy, pathology, radiotherapy)
• Hematologic Diseases (chemically induced)
• Humans
• Imidazoles (administration & dosage, adverse effects, therapeutic use)
• Lung Neoplasms (drug therapy, pathology, radiotherapy)
• Male
• Middle Aged
• Mouth Mucosa (drug effects, pathology)
• Nausea (chemically induced)
• Skin Diseases (chemically induced)
• Stomatitis (chemically induced)
• Treatment Outcome
• Tumor Cells, Cultured
• Vomiting (chemically induced)