title: Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination.
abstract: OBJECTIVE
  Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested utility in combining it with an HDAC inhibitor such as vorinostat. Thus, in this study in vitro studies assessed the potential utility of combining marizomib and vorinostat, followed by a clinical trial with the objectives of assessing the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), safety and preliminary anti-tumor activity of the combination in patients.
  
  
  METHODS
  Combinations of marizomib and vorinostat were assessed in vitro. Subsequently, in a Phase 1 clinical trial patients with melanoma, pancreatic carcinoma or Non-small Cell Lung Cancer (NSCLC) were given escalating doses of weekly marizomib in combination with vorinostat 300 mg daily for 16 days in 28 day cycles. In addition to standard safety studies, proteasome inhibition and pharmacokinetics were assayed.
  
  
  RESULTS
  Marked synergy of marizomib and vorinostat was seen in tumor cell lines derived from patients with NSCLC, melanoma and pancreatic carcinoma. In the clinical trial, 22 patients were enrolled. Increased toxicity was not seen with the combination. Co-administration did not appear to affect the PK or PD of either drug in comparison to historical data. Although no responses were demonstrated using RECIST criteria, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements.
  
  
  CONCLUSIONS
  Treatment of multiple tumor cell lines with marizomib and vorinostat resulted in a highly synergistic antitumor activity. The combination of full dose marizomib with vorinostat is tolerable in patients with safety findings consistent with either drug alone.
authors.affiliation: Sir Charles Gairdner Hospital, University of Western Australia, Perth, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.forename: Timothy
authors.initials: T
authors.lastname: Price
authors.forename: Amanda
authors.initials: A
authors.lastname: Townsend
authors.forename: Christopher
authors.initials: C
authors.lastname: Sweeney
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.forename: Shawgi
authors.initials: S
authors.lastname: Sukumaran
authors.forename: Angie
authors.initials: A
authors.lastname: Longenecker
authors.forename: Lonnie
authors.initials: L
authors.lastname: Lee
authors.forename: Ana
authors.initials: A
authors.lastname: Lay
authors.forename: Girish
authors.initials: G
authors.lastname: Sharma
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gemmill
authors.forename: Harry A
authors.initials: HA
authors.lastname: Drabkin
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.forename: Saskia T C
authors.initials: ST
authors.lastname: Neuteboom
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Spear
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007783:Lactones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D000077337:Vorinostat; C475865:marizomib
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