title: A randomized phase II trial of interleukin-2 in combination with four different doses of bryostatin-1 in patients with renal cell carcinoma.
abstract: OBJECTIVE
  Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer.
  
  
  METHODS
  IL-2 naïve patients were given 11 x 10(6) IU subcutaneously of IL-2 on days 1-4, 8-11, and 15-18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m2 of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m2. Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-gamma. Response evaluation was performed every 3 cycles.
  
  
  RESULTS
  Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88-120) and the median survival was 452 days (95% CI = 424-480). There was no significant boosting effect of Bryostatin-1 on lymphocytes.
  
  
  CONCLUSIONS
  The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Peterson
authors.forename: Helena
authors.initials: H
authors.lastname: Harlin
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: James A
authors.initials: JA
authors.lastname: Knost
authors.forename: John W
authors.initials: JW
authors.lastname: Kugler
authors.forename: Eric
authors.initials: E
authors.lastname: Lester
authors.forename: Everett
authors.initials: E
authors.lastname: Vokes
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D054713:Bryostatins / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D017211:Treatment Failure
chemical_list: D054713:Bryostatins; D016207:Cytokines; D007376:Interleukin-2; C046785:bryostatin 1