title: An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors.
abstract: BACKGROUND
  This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development.
  
  
  METHODS
  Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300-400 μg/mL) every 28 days plus 1,000 mg/m(2) gemcitabine HCl (days 1 and 15), 60 mg/m(2) docetaxel, 200 mg/m(2)/day temozolomide, 75 mg/m(2) cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*μg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*μg/mL for gemcitabine and erlotinib).
  
  
  RESULTS
  A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm.
  
  
  CONCLUSIONS
  The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.
authors.affiliation: Rocky Mountain Cancer Centers, Lone Tree, 10103 Ridgegate Pkwy Suite G01, Lone Tree, CO, 80124, USA, Robert.Jotte1@USOncology.com.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jotte
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Fadi
authors.initials: F
authors.lastname: Braiteh
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Becerra
authors.forename: Donald A
authors.initials: DA
authors.lastname: Richards
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.forename: Lawrence
authors.initials: L
authors.lastname: Garbo
authors.forename: Joe
authors.initials: J
authors.lastname: Stephenson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Conkling
authors.forename: Francisco
authors.initials: F
authors.lastname: Robert-Vizcarrondo
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: P Kellie
authors.initials: PK
authors.lastname: Turner
authors.forename: Kay Hoong
authors.initials: KH
authors.lastname: Chow
authors.forename: D Fritz
authors.initials: DF
authors.lastname: Tai
authors.forename: Robert
authors.initials: R
authors.lastname: Ilaria
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000077204:Temozolomide; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; C534068:N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide; D011799:Quinazolines; D013449:Sulfonamides; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D002945:Cisplatin; D000077204:Temozolomide; D000093542:Gemcitabine