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Practical Implementation of CRM in Real Clinical Settings for Oncology Dose-Finding Trials. Xiaobu Ye Sidney Kimmel Cancer Center, Biostatistics and Clinical Trials Johns Hopkins University School of Medicine. Talk Outline. How are we doing?
Sidney Kimmel Cancer Center, Biostatistics and Clinical Trials
Johns Hopkins University School of Medicine
How are we doing?
What might be the reasons?
What could we do to help?
Are there more challenges ahead ?
Dose-finding trials in oncology are a broad class of clinical experiments to determine an optimal dose (MTD or OBD) of drug for cancer related treatmentor prevention.
A higher therapeutic index for most cytotoxic drugs is obtained using a higher dose which yields higher side-effects
Definition of Dose-response relationship
The relationships among dose, drug concentration in blood, and clinical response (effectiveness and undesirable effects). ICH-E4
Model-based approaches are generally under some assumptions
CRM is one of the model-based approaches of dose-finding methods in oncology drug development, and was first proposed by O’Quigley et al (Biometrics, 1990)
From 1991-2006, among 1,235 phase I oncology trials in US, only 20 (1.6%) were identified using model based approach (A. Rogatko et al 2007)
There are three parties involved that created the reality:
To identify the necessary steps that ease the adaption of CRM into clinical practice (focus on “simplicity” for clinicians and safety for regulatory agency)
Working with investigators
Working with regulatory agency (CTEP)
Toxicity grading and modeling
working with investigators
detailed written documentation of model-based
dose selection process.
Henry Ford Hospital
Johns Hopkins University
Massachusetts General Hospital
Moffitt Cancer Center
NCI Neuro-Oncology Program
University of Alabama at Birmingham
University of Pennsylvania
Wake Forest University
NABTT-Consortium has been funded by the NCI since 1994 for therapeutic studies of central nervous system malignancies
Primary goal of the consortium is to improve the therapeutic outcome for adults with primary brain tumors.
The main task is early anti-cancer drug screen
includingdose-finding and safety / efficacy clinical trials
All NABTT trials
The main points in modification of CRM used in the NABTT :
The log-likelihood function for binomial outcomes and logistic dose response:
The best estimated dose is obtained by using pre-specified target toxicity rate and empirical data to fit the logistic function through maximum likelihood estimates of Beta and d50.
Reference: Piantadosi et al Practical implementation of a modified continual reassessment method for dose-finding trials, Cancer Chemother Pharmacol (1998)
Current website: http://www.cancerbiostats.onc.jhmi.edu/software.cfm
Potential future website:
1 working with investigators
The goal is to simplify and ease investigator’s participation
2. working with regulatory agency (CTEP)
The goal is to get approval of an algorithm rather than a set of pre-specified doses and demonstrate it is safe to perform a dose-find trial in human subjects using the algorithm
Currently, a reported safe dose from an on-going phase I trial in solid
tumors is XX.
Statisticians could help:
X number of patients were treated on dose level 1. Two patients had grade 4 thrombosis during first cycle of the treatment. One thrombosis was attributed to drug A with possible relationship given by the treating physician and it was deemed as a DLT based on pre-specified criteria. The other case of thrombosis was attributed as unlikely to either drug A or drug B given by a different treating physician. Due to this attribution, this case of thrombosis will be weighted as zero with respect to treatment related toxicity in estimation of next testing dose by CRM method.
The toxicity profile is attached to this report. Dr. X and statistician Y run the CRM model on <date> to obtain the next testing dose, dose level 2, for the group2. The new dose was reviewed by the central office on <date>.
Information should be provided in the statistical report:
The three parties in the challenging reality:
What are we looking for in a dose-finding trial?
A dose that has higher therapeutic effect for a medical condition and with tolerable side-effects
Mathematical models commonly used to fit dose-toxicity relationship for cytotoxic drugs are not necessarily suitable for describing the relationship of dose-biological activities unless the dose-biological function is similar to the relationship of dose-toxicity
The optimal biological dose based on a therapeutic end point :
The assays used to measure the biological effect need to be stabilized (sensitivity and variability assessment) and validated prior to the initiation of the phase I trial (E. Fox 2002).
These surrogate measures must be validated and correlated with the effect of the drug on the target in the tumor prior to using them as primary end points in clinical trials (KA. Gelmon, 1999)