Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors.
OBJECTIVE
Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations.


METHODS
Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival.


RESULTS
Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n=5) and cytotoxic (n=3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, <one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade≥3 nonhematologic and grade≥4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively.


CONCLUSIONS
Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA. gounderm@mskcc.org.
Mrinal M
MM
Gounder
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Lakshmi
L
Nayak
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Solmaz
S
Sahebjam
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Alona
A
Muzikansky
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Armando J
AJ
Sanchez
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Serena
S
Desideri
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Xiaobu
X
Ye
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
S Percy
SP
Ivy
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
L Burt
LB
Nabors
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Michael
M
Prados
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Stuart
S
Grossman
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Lisa M
LM
DeAngelis
Mrinal M. Gounder, Armando J. Sanchez, and Lisa M. DeAngelis, Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical School, New York, NY; Lakshmi Nayak and Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School; Alona Muzikansky, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Solmaz Sahebjam, Moffitt Cancer Center, University of South Florida, Tampa, FL; Serena Desideri, Xiaobu Ye, and Stuart Grossman, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore; S. Percy Ivy, National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, MD; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; and Michael Prados, University of California at San Francisco, San Francisco, CA.
Patrick Y
PY
Wen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D016208:Databases, Factual; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D061214:Patient Safety; D018579:Patient Selection; D012074:Remission Induction; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents