Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities.
OBJECTIVE
Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution.


METHODS
Individual patient records from 38 phase I studies activated between 2000 and 2010 were used. Dose was defined as a percentage of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All P values were two-sided.


RESULTS
11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (P = 0.0920 for grade ≥ 3, P = 0.4194 for grade ≥ 1), whereas related toxicity increased with dose (P < 0.0001, both grade ≥ 3 and ≥ 1). Similar results were observed across toxicity categories. In the five-tier system, toxicities attributed as "possibly," "probably," or "definitely" related were associated with dose (all P < 0.0001), whereas toxicities attributed as "unlikely" or "unrelated" were not (all P > 0.1).


CONCLUSIONS
Reassuringly, we did not observe an association between unrelated toxicity rate and dose, an association that could only have been explained by physician misattribution. Our findings also confirmed our expectation that related toxicity rate increases with dose. Our analysis supports simplifying attribution to a two-tier system by collapsing "possibly," "probably," and "definitely" related.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Anne
A
Eaton
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
Alexia
A
Iasonos
Weill Cornell Medical College, New York, New York. Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Mrinal M
MM
Gounder
Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Erika G
EG
Pamer
Weill Cornell Medical College, New York, New York. Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Alexander
A
Drilon
Theradex Systems, Inc., Princeton, New Jersey.
Diana
D
Vulih
The National Cancer Institute, Bethesda, Maryland.
Gary L
GL
Smith
The National Cancer Institute, Bethesda, Maryland.
S Percy
SP
Ivy
Weill Cornell Medical College, New York, New York. Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
David R
DR
Spriggs
Weill Cornell Medical College, New York, New York. Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. hymand@mskcc.org.
David M
DM
Hyman
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000145:classification; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology; D055815:Young Adult
D000970:Antineoplastic Agents