title: Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute.
abstract: BACKGROUND
  Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time.
  
  
  METHODS
  A retrospective analysis was performed on 711 adult AML patients enrolling in 45 phase I clinical trials supported by the Cancer Therapy Evaluation Program of the National Cancer Institute from 1986 to 2009. Changes in ORR and mortality rates for patients enrolled in 1986 to 1990, 1991 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009 were estimated with multivariable logistic regression models. All statistical tests were two-sided.
  
  
  RESULTS
  There was a statistically significant increase in AML patients enrolling in phase I clinical trials over time (1986 to 1990: n = 61; 2006 to 2009: n = 256; P = .03). The ORR for the entire cohort was 15.4% (1986 to 1990: 8.9%, 1991 to 1995: 21.1%; 1996 to 2000: 7.0%; 2001 to 2005: 10.0%; 2006 to 2009: 22.6%), and it statistically significantly improved over time (P < .001). There was a statistically significant improvement in ORRs with novel agents in combination vs single agents (ORR = 22.8% vs 4.7%, respectively, odds ratio = 5.95, 95% confidence interval = 3.22 to 11.9, P < .001). The 60-day mortality rate for the entire cohort was 22.6%, but it statistically significantly improved over time (P = .009).
  
  
  CONCLUSIONS
  There has been an encouraging increase in AML patients enrolling in phase I clinical studies over time. The improvement in ORRs appears to be partly because of the increase in combination trials and the inclusion of previously untreated poor-risk AML. Continued enrollment of AML patients in early phase clinical trials is vital for drug development and improvement in therapeutic outcomes.
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Zeidner
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Blackford
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Foster
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: Gary
authors.initials: G
authors.lastname: Smith
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: Affiliations of authors: University of North Carolina, Lineberger Comprehensive Cancer Center , Chapel Hill, NC (JFZ, MCF, ECD); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , Baltimore, MD (JEK, ALB); Cancer Therapy Evaluation Program , National Cancer Institute , Rockville, MD (GS, SPI, PH) .
authors.forename: Pamela
authors.initials: P
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D016017:Odds Ratio; D018579:Patient Selection; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D000970:Antineoplastic Agents