title: A phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors.
abstract: BACKGROUND
  Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active.
  
  
  RESULTS
  Twenty-nine heavily pretreated patients [median 3 [0-7]] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m(2) q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). A trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses.
  
  
  METHODS
  Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m(2)), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics and disease outcome.
  
  
  CONCLUSIONS
  The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m(2) q3weeks, respectively. The combination is tolerable and has potential antitumor activity.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. nazad2@jhmi.edu
authors.forename: Nilofer
authors.initials: N
authors.lastname: Azad
authors.forename: Alyssa
authors.initials: A
authors.lastname: Perroy
authors.forename: Erin
authors.initials: E
authors.lastname: Gardner
authors.forename: Chiyo K
authors.initials: CK
authors.lastname: Imamura
authors.forename: Cynthia
authors.initials: C
authors.lastname: Graves
authors.forename: Gisele A
authors.initials: GA
authors.lastname: Sarosy
authors.forename: Lori
authors.initials: L
authors.lastname: Minasian
authors.forename: Herbert
authors.initials: H
authors.lastname: Kotz
authors.forename: Miranda
authors.initials: M
authors.lastname: Raggio
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D014230:Triazoles; C062058:carboxyamido-triazole; D017239:Paclitaxel