title: Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer.
abstract: BACKGROUND
  Bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors.
  
  
  METHODS
  Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500-600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7-1.3 mg/m2 on D1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0-1.6 mg/m2 on D1 and 8).
  
  
  RESULTS
  We treated 27 patients on four dose levels in arm A and three dose levels in arm B. Tumor types included lung (n = 16), adenoid cystic carcinoma (n = 2), prostate (n = 2), sarcoma (n = 2), breast (n = 1), thymus (n = 1), head and neck (n = 1), and gastrointestinal(n = 2). Dose-limiting toxicities were seen in arm A only; grade 3 asthenia (n = 2), grade 3 transaminitis and dehydration (n = 1). The most common grade 3/4 toxicity was neutropenia. Of 26 evaluable patients, 2 patients had partial response (1 in arm A and 1 in arm B), 13 had stable disease (7 in arm A and 6 in arm B), and 11 had progression (6 in arm A and 5 in arm B). Of the 16 patients with non-small cell lung cancer, 2 (12.5%) had partial response and 9 had stable disease, for a disease control rate of 68.8%. Recommended phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly.
  
  
  CONCLUSIONS
  Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses. Based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.
authors: University of California, Davis Cancer Center, Sacramento, California 95817, USA. angela.davies@ucdmc.ucdavis.edu
authors: Angela M
authors: AM
authors: Davies
authors: Cheryl
authors: C
authors: Ho
authors: Alex S
authors: AS
authors: Metzger
authors: Laurel A
authors: LA
authors: Beckett
authors: Scott
authors: S
authors: Christensen
authors: Michael
authors: M
authors: Tanaka
authors: Primo N
authors: PN
authors: Lara
authors: Derick H
authors: DH
authors: Lau
authors: David R
authors: DR
authors: Gandara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D000068437:Pemetrexed; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis
chemical_list: D001897:Boronic Acids; D005971:Glutamates; D011719:Pyrazines; D000068437:Pemetrexed; D006147:Guanine; D000069286:Bortezomib