Abstract
Patients who do not complete one cycle of therapy on Phase I trials for reasons other than dose limiting toxicity (DLT) are considered inevaluable for toxicity and must be replaced. Individual records from patients enrolled to NCI-sponsored Phase I trials activated between 2000 and 2010 were used. Early discontinuation was defined as the failure to begin cycle 2 for reasons other than a DLT during cycle 1. A multinomial logistic regression with a 3-level nominal outcome (early discontinuation, DLT during cycle 1, and continuation to cycl1e 2) was used with continuation to cycle 2 serving as the reference category. The final model was used to create two risk scores. An independent external cohort was used to validate these models. Data from 3079 patients on 127 Phase I trials were analyzed. ECOG performance status (1, ≥ 2, two-sided P = .0315 and P = .0007), creatinine clearance (<60 ml/min, P = .0455), alkaline phosphatase (>2.5xULN, P = .0026), AST (>ULN, P = .0076), hemoglobin (<10 g/dL, P < .0001), albumin (<3.5 g/dL, P < .0001), and platelets (<400x109/L, P = .0732) were predictors of early discontinuation. The c-index of the final model was 0.63. Knowledge of risk factors for early treatment discontinuation in conjunction with clinical judgment can help guide Phase I patient selection.
Highlights
Phase I eligibility criteria are intended to select fit patients with good performance status, near normal organ function, and minimal co-morbidities in order to accurately characterize the toxicity of the investigational drug [1,2,3,4,5]
Patients who do not complete at least one cycle of therapy on Phase I trials for reasons other than dose limiting toxicity (DLT) are typically considered inevaluable for toxicity and must be replaced [15]
In order to address this unmet need, we analyzed the individual patient records from a large cohort of 3079 patients enrolled to 127 National Cancer Institute (NCI)-sponsored Phase I clinical trials from 67 institutions throughout North America with the aim of identifying risk factors and developing a risk score for early discontinuation
Summary
Phase I eligibility criteria are intended to select fit patients with good performance status, near normal organ function, and minimal co-morbidities in order to accurately characterize the toxicity of the investigational drug [1,2,3,4,5]. 16% of patients enrolled to Phase I trials discontinued protocol therapy within the first 21 days of beginning treatment [7]. Prognostic risk scores are available to estimate the 90day overall survival of Phase I trial participants, little is known about what factors put patients at risk for early trial discontinuation. No risk score or predictive model is available to estimate the risk of early discontinuation among Phase I eligible patients. In order to address this unmet need, we analyzed the individual patient records from a large cohort of 3079 patients enrolled to 127 National Cancer Institute (NCI)-sponsored Phase I clinical trials from 67 institutions throughout North America with the aim of identifying risk factors and developing a risk score for early discontinuation
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