title: A phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer.
abstract: BACKGROUND
  Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis.
  
  
  METHODS
  Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0-2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m(2) on days 1, 8, and 15 along with bryostatin-1 50 microg/m(2) on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled.
  
  
  RESULTS
  Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1-4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4-49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-alpha after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel.
  
  
  CONCLUSIONS
  This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.
authors.affiliation: The Department of Medicine, Section of Hematology and Oncology, University of Chicago Medical Center, University of Chicago Cancer Center and the Phase II Network, 5841 S Maryland Avenue MC2115, Chicago, IL 60637, USA.
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Winegarden
authors.forename: Ann M
authors.initials: AM
authors.lastname: Mauer
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hoffman
authors.forename: Stuart
authors.initials: S
authors.lastname: Krauss
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000556:secondary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D054713:Bryostatins; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007783:Lactones / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D018942:Macrolides; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011292:Premedication; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054713:Bryostatins; D005938:Glucocorticoids; D015850:Interleukin-6; D007783:Lactones; D018942:Macrolides; D014409:Tumor Necrosis Factor-alpha; C046785:bryostatin 1; D017239:Paclitaxel