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Clinical Trials |
Department of Radiation Oncology [S. M. H., E. J. B., D. S., W. G. M.], Department of Pathology and Laboratory Medicine [R. J. M.], Department of Medicine, and Division of Hematology Oncology [D. G. H., J. P. S.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283; Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536 [W. R., M. M.]; Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27599 [J. T.]; Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114 [T. F. D.]; Department of Radiation Oncology, Northwestern Memorial Hospital, Chicago, Illinois 60611 [K. D. K.]; and Merck Research Laboratory, Rahway, New Jersey 07065 [B. P., B. M., P. D.]
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.
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