title: Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors.
abstract: OBJECTIVE
  Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence.
  
  
  METHODS
  Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles.
  
  
  RESULTS
  Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 microg/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo.
  
  
  CONCLUSIONS
  Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.
authors.affiliation: New York University School of Medicine, New York University Cancer Institute, New York, NY, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wu
authors.forename: John
authors.initials: J
authors.lastname: Roberts
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rosenthal
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Scott
authors.initials: S
authors.lastname: Wadler
authors.forename: Kathleen
authors.initials: K
authors.lastname: Farrell
authors.forename: Michelle
authors.initials: M
authors.lastname: Carr
authors.forename: David
authors.initials: D
authors.lastname: Fry
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Ruth
authors.initials: R
authors.lastname: Oratz
authors.forename: Howard
authors.initials: H
authors.lastname: Hochster
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
authors.forename: Franco
authors.initials: F
authors.lastname: Muggia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054713:Bryostatins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011493:Protein Kinase C / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; C046785:bryostatin 1; D011493:Protein Kinase C; D002945:Cisplatin