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["Design Type"]
[]
[]
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[]
[null,"Accelerated  Titration  Designs for  Phase I Clinical Trials"]
[null,"Biometric Research Branch, NCI"]
[]
[null,"Warning:  this program provides only general guidance related to proposed "]
[null,"  accelerated  titration designs for phase I clinical trials. It is not meant"]
[null,"to substitute for professional medical judgement in the treatment of"]
[null,"individual patients. All dose level assignments should be verified"]
[null," independently.  In addition, while an effort was made to accommodate"]
[null,"minor deviations  from the recommended dose, failure to follow the "]
[null," recommended dose schedule may invalidate the future dose "]
[null," recommendations. "]
[]
[null,"This  program  provides  assistance  in  dose  level  assignment  for            "]
[null,"Accelerated  Titration  Designs   for  Phase I  Clinical  Trials   "]
[null,"[Simon,  Freidlin,  Rubinstein,  Arbuck,  Collins,  Christian "]
[null,"Journal of National Cancer Institute 1997;  89  1138-47]. For additional"]
[null,"assistance or clarification, Drs. Richard Simon (rs10m@nih.gov) and"]
[null,"Larry Rubinstein (rubinstein@ctep.nci.nih.gov) are available."]
[]
[]
[null,"Brief Description of Accelerated Titration Design 2"]
[]
[null,"The  dose escalation/de-escalation rules for design 2 are based on generic"]
[null,"definitions of life threatening toxicity (LT), dose limiting toxicity (DLT),  "]
[null,"moderate' toxicity (MOD), 'mild' toxicity (MILD) and no toxicity (NONE)."]
[null,"Definitions of these events must be specified for each protocol for Phase I "]
[null,"clinical trials."]
[]
[null,"The method used for dose assignment for the first course of a new patient"]
[null,"depends on whether the patient is entered during the early accelerated mode"]
[null,"or the later standard mode of the trial. During the early mode, there is one "]
[null,"patient per cohort, and the dose for each patient is one dose level (a factor of "]
[null,"1.4) higher than that used for the first course of the previous patient. The "]
[null,"accelerated mode ends when one patient experiences DLT or worse during the "]
[null,"first course of treatment or when two patients experience 'moderate' toxicity "]
[null,"during the first course of treatment."]
[]
[null,"When the accelerated mode ends, the dose assignment for the first course"]
[null,"of a new patient is the same as that of the standard Phase I design. Two  "]
[null,"additional patients are placed on the dose level at which the last new patient "]
[null,"was treated, and subsequently, cohorts of three to six patients are started at  "]
[null,"each dose level. If zero of three experience first course DLT or worse, the next   "]
[null,"cohort starts one dose level higher (a multiplicative factor of 1.4). If one of three "]
[null,"experience first course DLT or worse, up to three more patients are started at  "]
[null,"the same dose level. If two or more experience first course DLT or worse, no "]
[null,"further patients are started at that dose. The largest dose level at which less"]
[null,"than two patients experience first course DLT or worse is expanded to six "]
[null,"patients."]
[]
[null,"The intra-patient dose modification options are defined as follows:"]
[null,"Option A: "]
[null,"No  intra-patient dose escalation. "]
[null,"If the worst toxicity is DLT or worse during a course, the dose is reduced one  "]
[null,"dose level for the next course of that patient."]
[null,"Option B: "]
[null,"If the worst toxicity is DLT or worse during a course, the dose is reduced one  "]
[null,"dose level for the next course of that patient. If the worst toxicity is 'moderate'  "]
[null,"the dose level remains the same for the next course. If the worst toxicity is less"]
[null,"than 'moderate', the dose is increased one level for the next course. "]
[]
[]
[null,"Brief Description of Accelerated Titration Design 4"]
[]
[null,"The dose escalation/de-escalation rules for design 4 also assume that there "]
[null,"are protocol-specific definitions of life threatening (LT), DLT, 'moderate',  'mild'  "]
[null,"and no toxicity. Single dose steps represent 40%  increments (as above),"]
[null,"but during the early acceleration phase of the trial, double dose steps are used "]
[null,"(approximately 100% increments; 1.4 x 1.4)."]
[]
[null,"The method used for a dose level assignment for the first course of a new "]
[null,"patient depends on whether the patient enters during the early accelerated"]
[null,"mode or the later standard mode of the trial. During the early mode, there is  "]
[null,"one patient per cohort and the first-course dose for each patient is twice the"]
[null,"dose used for the first course of the previous patient. The accelerated mode "]
[null,"ends when one patient experiences DLT or worse during any course of  "]
[null,"treatment or when two different patients experience 'moderate' toxicity during  "]
[null,"any course of treatment (so long as the dose level does not exceed that of the "]
[null,"first course of the most recent patient). The accelerated mode is suspended "]
[null,"when the initial instance of 'moderate' toxicity occurs (so long as the dose "]
[null,"level does not exceed that of the first course of the most recent patient), "]
[null,"if  two additional patients have not been treated at that dose level, or higher,"]
[null,"with no worse than mild toxicity. During the suspension, the dose is assigned"]
[null,"for new patients, or for additional courses of ongoing patients, as in the non-"]
[null,"accelerated phase (except that ongoing patients treated below the level at "]
[null,"which moderate toxicity was seen continue to be escalated as in the "]
[null,"accelerated mode).  The suspension is resolved by resuming acceleration"]
[null,"if two patients (other than the one who had toxicity which triggered the "]
[null,"the suspension), treated at the current dose, or higher,  for any course, show "]
[null,"no worse than mild toxicity. Otherwise, the suspension will be resolved by"]
[null,"ending acceleration, since there will have been a case of DLT or two cases"]
[null,"of 'moderate' toxicity."]
[]
[null,"When the accelerated mode ends, the dose assignment for the first course of"]
[null,"a new patient is the same as that of the standard method described above "]
[null,"under Design 2."]
[]
[null,"The intra-patient dose modification options are defined as follows: "]
[null,"Option A: "]
[null,"No  intra-patient dose escalation. "]
[null,"If the worst toxicity is DLT or worse during a course, the dose is reduced one  "]
[null,"dose level for the next course of that patient."]
[null,"Option B: "]
[null,"If the worst toxicity is DLT or worse during a course, the dose is reduced one  "]
[null,"dose level for the next course of that patient. If the worst toxicity is 'moderate'  "]
[null,"the dose level remains the same for the next course. If the worst toxicity is less"]
[null,"than 'moderate', the dose is increased for the next course. The increase is two  "]
[null,"dose levels during the early accelerated mode of the trial, and one dose level"]
[null,"otherwise"]
[]
[null,"Spreadsheet Layout"]
[]
[null,"Each row corresponds to one patient. It contains a patient ID field and a"]
[null,"section for each treatment course. The program supports up to ten courses"]
[null,"per patient. Each course section consists of four columns: the date the course"]
[null,"begins, the administered dose level, the recommended dose level, and the "]
[null,"worst toxicity. The 'worst toxicity' is defined to be the severity of the worst"]
[null,"toxicity in any organ system, judged to be definitely or probably drug related,"]
[null,"and observed for that treatment course in that patient. "]
[]
[null," NA means not expected to ever be available (e.g., due to the"]
[null,"death of the patient from non-drug related causes)."]
[]
[]
[null,"Operating Instructions"]
[]
[null,"A separate Excel workbook file must be used for each Phase I trial. Files"]
[null,"for different phase I trials must be saved under different file names, to avoid"]
[null,"overwriting previously accumulated data. The main spreadsheet in each"]
[null,"workbook must be initially devoid of data from any other trial or test."]
[]
[null,"To begin using the program, enter a protocol identifier (up to 8 characters) and"]
[null,"a design (2A, 2B, 4A or 4B). When a new patient has consented to treatment, "]
[null,"a dose level recommendation is obtained  by clicking on an \"Assign dose level\" "]
[null,"button. The program will request a patient identifier. A patient identifier may be "]
[null,"any label up to 8 characters. The program will then provide the recommended "]
[null,"dose level, according to the design used, for the first course of the new patient."]
[null,"The program automatically records the recommended dose level in the "]
[null,"appropriate column for the new patient. At that point you may save the updated"]
[null,"spreadsheet and exit.  "]
[]
[null,"Between runs of the spreadsheet macro, you should update the fields giving  "]
[null,"start dates of the treatment courses, dose levels actually administered, and  "]
[null,"worst toxicities for all previously entered patients. The program checks that: (a)  "]
[null,"all patients' courses for which recommended dose level have been assigned  "]
[null,"have been updated with start dates and administered dose levels; and (b) that      "]
[null,"all courses starting more than 30 days before the current date contain worst "]
[null,"toxicity evaluation. (Dates must be  given in mm/dd/yy form)."]
[]
[null,"The program will also recommend dose levels for subsequent courses of"]
[null,"previously entered patients. After clicking on the \"Assign dose level\" button "]
[null,"when prompted for patient identification, provide the ID of a previously entered "]
[null,"patient."]
[]
[null,"The program works based on dose level, not dose. It assumes that the protocol"]
[null,"defines  the dose levels based on approximately 40% increments."]
[]
[null,"It is important that the information entered into the worst toxicity fields be"]
[null,"based on careful assessment and complete observation of the at-risk period"]
[null,"(at least 15 days). The observation of dose limiting toxicity, however, should be "]
[null,"recorded as soon as it is observed even if at-risk period has not been "]
[null,"completed. No  lower grades of toxicity should  be recorded, however, until "]
[null,"the full at-risk period has been completed. If a patient is not evaluated for "]
[null,"toxicity because of death (not drug related) or inaccessibility, the worst toxicity"]
[null,"should be recorded as NA (not available). Toxicities should be recorded using"]
[null,"one of the following short codes: LT, DLT, MOD, MILD, NONE or NA.   Either"]
[null,"upper or lower case characters may be entered, but will be converted to upper"]
[null,"case."]

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