title: Successful implementation of the randomized discontinuation trial design: an application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma--CALGB 69901.
abstract: OBJECTIVE
  To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design.
  
  
  METHODS
  Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups.
  
  
  RESULTS
  A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted.
  
  
  CONCLUSIONS
  CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents.
authors.affiliation: University of Chicago, Section of Hematology/Oncology, 5841 S Maryland Ave, MC-2115, Chicago, IL 60637, USA. wstadler@medicine.bsd.uchicago.edu
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Gary
authors.initials: G
authors.lastname: Rosner
authors.forename: Eric
authors.initials: E
authors.lastname: Small
authors.forename: Donna
authors.initials: D
authors.lastname: Hollis
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.forename: S Donald
authors.initials: SD
authors.lastname: Zaentz
authors.forename: John
authors.initials: J
authors.lastname: Mahoney
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012107:Research Design; D015996:Survival Rate; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014230:Triazoles; C062058:carboxyamido-triazole