title: A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer.
abstract: 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.
authors: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA. hahn@xrt.upenn.edu
authors: Stephen M
authors: SM
authors: Hahn
authors: Eric J
authors: EJ
authors: Bernhard
authors: William
authors: W
authors: Regine
authors: Mohammed
authors: M
authors: Mohiuddin
authors: Daniel G
authors: DG
authors: Haller
authors: James P
authors: JP
authors: Stevenson
authors: Debbie
authors: D
authors: Smith
authors: Barnali
authors: B
authors: Pramanik
authors: Joel
authors: J
authors: Tepper
authors: Thomas F
authors: TF
authors: DeLaney
authors: Krystina D
authors: KD
authors: Kiel
authors: Briggs
authors: B
authors: Morrison
authors: Paul
authors: P
authors: Deutsch
authors: Ruth J
authors: RJ
authors: Muschel
authors: W Gillies
authors: WG
authors: McKenna
mesh_terms: 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
chemical_list: D007093:Imidazoles; C425231:L 778,123; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase