Research to evaluate the relation of toxicity and the relative dose intensity in phase I trials beyond cycle 1 of Molecular Targeted Agents (MTAs)

The primary endpoint of this study is relative dose intensity (RDI) for all the courses treated, i.e., the longitudinal RDI. We used the random slope mixed effect model to estimate the impact of the dose level tested on the longitudinal RDI in each phase I trial. The random slope mixed effect model includes the fixed effects of dose level, treatment course, interaction of dose level and treatment course and the random effect of the intercept and slope. The unstructured covariance matrix will be used. This analysis will be performed using the PROC MIXED procedure in SAS 9.3.If the longitudinal RDI tends to decrease as increasing the number of courses in the recommended phase II dose (RP2D) indentified in that trial, it may indicate that the RP2D should be determined based on not only the toxicity data in the first course but also that in the subsequent courses.Secondary analysis for primary endpointWe categorize the dose levels tested into the two groups, acceptable toxicity dose group (ATDG) and unacceptable toxicity dose group (UTDG). The ATDG is defined as the dose group whose dose level is lower or equal to the RP2D, while The UTDG is defined as that whose dose level is higher than the RP2D. Since we suppose that the trends of the longitudinal RDI decline between the two groups may be different, the difference of slope for longitudinal RDI between the two groups is compared using the random slope mixed effect model with unstructured covariance matrix.Exploratory analysisWe evaluate the impact of the longitudinal RDI on the progression free survival (PFS). To this end, we perfume the Cox regression model including the dose level and the RDI in each course as time-varying variable. If the significant impact of RDI on the PFS is found, our hypothesis that the RP2D should be determined based on not only the toxicity data in the first course but also that in the subsequent courses will also be supported.Covariate adjustment and subgroup analysisThe above-mentioned analyses are also employed with adjustments for covariates such as cancer type (e.g., solid or hematologic), drug type (e.g., cytotoxic agents or molecularly targeted agents), race (e.g., White, Black, Native Hawaiian or Other Pacific Islander, Asian, mixed, Unknown) as well as in the subgroup of these variables.Other considerationsFor each course in each trial, we investigate the presence/absence of dose limiting toxicity (DLT), grade of adverse events (i.e., mild, moderate, severe, life-threatening, fatal), and the action (e.g., none, dose reduction, regimen interrupted, therapy discontinued, interrupted and then reduced), and response (i.e., progression disease, stable disease, partial response, complete response), performance status (i.e., 0, 1, 2).SupplementaryWe conducted these analyses using the data from 16 phase I trials of the Cancer Therapy Evaluation Program (CTEP) sponsored by the National Cancer Institute. All the trials were the dose-finding trials for the use of single MTA. In almost trials, it was demonstrated that the RDI decreases with increasing the course in each dose level. Furthermore, this decline of RDI was associated with higher risk of progression disease.Also we have listed below the needed datasets:Protocol IDPatient IDRegistration DateTreatment Assignment Description Code (Regimen code)Course NumberStart Date of CourseDate of First Treatment in each Subject (The first day of administration in the first course)Planned Duration of Course (Day)Actual Total Dose for each CourseRelative Dose Intensity (RDI) per CourseRDI Change from Baseline in that CourseNumber of Dose Limiting Toxocity (DLT) Event per CourseDate of 1st Occurance of DLT in each SubjectMaximum Advers Event (AE) Grade in that CourseDate of 1st Occurance of Grades 3, 4, or 5 AEAction for each AE (e.g., none, Dose reduced, Regimen interrupted, Therapy discontinued, Interrupted and then reduced) in that CourseAction for each DLT (e.g., none, Dose reduced, Regimen interrupted, Therapy discontinued, Interrupted and then reduced) in that CourseThe number of Grade 1 (Mild) AE in that CourseThe number of Grade 2 (Moderate) AE in that CourseThe number of Grade 3 (Severe) AE in that CourseThe number of Grade 4 (Life_Threatening) AE in that CourseThe number of Grade 5 (Fatal) AE in that CourseStart Date of the Last Course in each SubjectDate of Last Treatment in each Subject (The last day of administration in the last course)Response Assessment in that Course (CR, PR, SD, PD, NE)Date of Evaluation of Best Response in that CourseDate of Evaluation of Progression in that CourseDate of Off TreatmentThe Reason for Study FinishedMaxmimum Tolerated Dose (or Recommended Phase 2 Dose) determinedDeath on Study or notDate of Death on StudySexAgeEthnicityRacePrimary SiteStageHistology/CytopathologyPerformance StatusHeight at Start of the CourseBody Weight at Start of the CourseBSA at Start of the CourseName of Study Concomitant Drug 1, if any