title: Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors.
abstract: BACKGROUND
  Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors.
  
  
  METHODS
  The primary objectives of this study were to determine dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a cabazitaxel/cisplatin combined regimen (Part 1) and to assess antitumor activity at the MTD (Part 2). Safety and pharmacokinetics (PK) were also examined.
  
  
  RESULTS
  Twenty-five patients with advanced solid tumors were enrolled (10 in Part 1; 15 in Part 2). In Part 1, two dose levels were evaluated; the MTD for cabazitaxel/cisplatin (given Q3W) was 15/75 mg/m(2). DLTs occurring during Cycle 1 at the maximum administered dose (20/75 mg/m(2); acute renal failure and febrile neutropenia) and the MTD (febrile neutropenia and hypersensitivity despite pre-medication) were as expected for taxane/platinum combinations. For the 18 patients treated at the MTD, the most frequent possibly related non-hematologic treatment-emergent adverse events (Grade ≥ 3) were nausea (16.7%), fatigue, acute renal failure and decreased appetite (each 11.1%). Neutropenia was the most frequent treatment-emergent Grade ≥ 3 hematologic laboratory abnormality at the MTD (77.8%). The best overall response at the MTD was stable disease, observed in 66.7% of patients. PK results of the combination did not appear to differ from single-agent administration for each agent.
  
  
  CONCLUSIONS
  Combination treatment with cabazitaxel/cisplatin had a manageable safety profile; no PK interactions were evident. The recommended Phase II dose for this combination is cabazitaxel/cisplatin 15/75 mg/m(2) administered every 3 weeks. Antitumor activity findings suggest that further evaluation of this combination in disease-specific trials is warranted.
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8056, St. Louis, MO, 63110, USA, alockhar@dom.wustl.edu.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Shankar
authors.initials: S
authors.lastname: Sundaram
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moseley
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Barber
authors.forename: Alex R
authors.initials: AR
authors.lastname: Lane
authors.forename: Claudine
authors.initials: C
authors.lastname: Wack
authors.forename: Laurent
authors.initials: L
authors.lastname: Kassalow
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dedieu
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D066066:Response Evaluation Criteria in Solid Tumors; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D043823:Taxoids; C552428:cabazitaxel; D002945:Cisplatin