title: Phase I study of prolonged infusion Bryostatin-1 in patients with advanced malignancies.
abstract: OBJECTIVE
  Bryostatin-1 is a compound known to inhibit protein kinase C expression. Clinical trials have focused on administration schedules ranging from 1 hour to 72 hour infusions. Preclinical data suggest that the down regulation of the target PKC occurs only as long as the drug is being infused. Therefore we performed a phase 1 clinical trial to determine the safety and recommended dose of prolonged infusion Bryostatin-1.
  
  
  METHODS
  Patients with advanced metastatic cancer were enrolled in this traditional phase 1 clinical trial utilizing prolonged infusion Bryostatin-1. The administration of Bryostatin-1 was initially begun at 96 hours and extended to 14 days. Doses were escalated using the 96 hour infusion time and then duration of infusion was increased. All patients underwent extensive sampling for determination of PKC levels as well as other key biologic end points. The determination of maximum tolerated dose and recommended phase two dose were based on toxicity.
  
  
  RESULTS
  38 patients were enrolled in the study. The recommended phase two doses were 24 mcg/m2 over five days, 16 mcg/m2 over six days and 8 mcg/m2 over 14 days. At the higher dose levels we demonstrated consistent down regulation of PKC-alpha. This was not observed at the low dose level. Toxicities were limited to myalgias and fatigue and were dose-related. The results of downstream signaling effects were less clear. MMP expression was not altered by treatment with Bryostatin-1. Only limited evidence for alterations in PKC activity as measured by expression of phosphorylated MAPK was observed. No objective responses were observed with five patients having prolonged stabilization of disease.
  
  
  CONCLUSIONS
  Bryostatin-1 is safely administered over prolonged infusion schedules. There appears to be a dose response for PKC inhibition. Bryostatin-1 is a complicated compound as is the target PKC and its related signaling pathways. There is only limited clinical activity with this compound as a single agent; future studies should focus on combinations with other cytotoxics or targeted therapies.
authors.affiliation: Lombardi Cancer Center, Georgetown University Medical Center, Washington DC 20007, USA. marshalj@georgetown.edu
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Neelesh
authors.initials: N
authors.lastname: Bangalore
authors.forename: Dorraya
authors.initials: D
authors.lastname: El-Ashry
authors.forename: Yair
authors.initials: Y
authors.lastname: Fuxman
authors.forename: Michael
authors.initials: M
authors.lastname: Johnson
authors.forename: Brian
authors.initials: B
authors.lastname: Norris
authors.forename: Michael
authors.initials: M
authors.lastname: Oberst
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ness
authors.forename: Slawomir
authors.initials: S
authors.lastname: Wojtowicz-Praga
authors.forename: Pankaj
authors.initials: P
authors.lastname: Bhargava
authors.forename: Naiyer
authors.initials: N
authors.lastname: Rizvi
authors.forename: Said
authors.initials: S
authors.lastname: Baidas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hawkins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D054713:Bryostatins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007783:Lactones / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D020935:MAP Kinase Signaling System; D018942:Macrolides; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000097:blood; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D020033:Protein Isoforms; C046785:bryostatin 1; C081975:protein kinase C eta; C496628:PRKCA protein, human; C497258:PRKCD protein, human; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D020780:Matrix Metalloproteinase 9