title: Identifying clinical improvement in consolidation single-arm phase 2 trials in patients with ovarian cancer in second or greater clinical remission.
abstract: OBJECTIVE
  Estimates of progression-free survival (PFS) from single-arm phase 2 consolidation/maintenance trials for recurrent ovarian cancer are usually interpreted in the context of historical controls. We illustrate how the duration of second-line therapy (SLT), the time on the investigational therapy (IT), and patient enrollment plan can affect efficacy measures from maintenance trials and might result in underpowered studies.
  
  
  METHODS
  Efficacy data from 3 published single-arm consolidation therapies in second remission in ovarian cancer were used for illustration. The studies were designed to show an increase in estimated median PFS from 9 to 13.5 months. We partitioned PFS as the sum of the duration of SLT, treatment-free interval, and duration of IT. We calculated the statistical power when IT is given concurrently with SLT or after SLT by varying the start of IT. We compared the sample sizes required when PFS includes the time on SLT versus PFS that starts after SLT at initiation of IT.
  
  
  RESULTS
  Required sample sizes varied with duration of SLT. If IT starts with initiation of SLT, only 34 patients are needed to provide 80% power to detect a 33% hazard reduction. In contrast, 104 patients are required for a single-arm study for 80% power, if IT begins 7.5 months after SLT initiation.
  
  
  CONCLUSIONS
  Designs of nonrandomized consolidation trials that aim to prolong PFS must consider the effect of the duration of SLT on the end point definition and on required sample size. If IT is given concurrently with SLT, and after SLT, then SLT duration must be restricted per protocol eligibility, so that a comparison with historical data from other single-arm phase 2 studies is unbiased. If IT is given after SLT, the duration of SLT should be taken into account in the design stage because it will affect statistical power and sample size.
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. iasonosa@mskcc.org
authors.forename: Alexia
authors.initials: A
authors.lastname: Iasonos
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: Carol A
authors.initials: CA
authors.lastname: Aghajanian
authors.forename: Roisin E
authors.initials: RE
authors.lastname: O'Cearbhaill
authors.forename: Martee L
authors.initials: ML
authors.lastname: Hensley
authors.forename: Howard T
authors.initials: HT
authors.lastname: Thaler
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015982:Bias; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000706:statistics & numerical data; D060830:Consolidation Chemotherapy; D003627:Data Interpretation, Statistical; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D018579:Patient Selection; D012008:Recurrence; D012074:Remission Induction; D012107:Research Design; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
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