• Corpus ID: 18648350

Extending the TITE CRM to Multiple Outcomes with Application to a Phase 1 Clinical Trial in Canine Hemangiosarcoma

  title={Extending the TITE CRM to Multiple Outcomes with Application to a Phase 1 Clinical Trial in Canine Hemangiosarcoma},
  author={Joseph S. Koopmeiners and Jaime F. Modiano},
In traditional phase 1 oncology trials, the safety of a new chemotherapeutic agent is tested in a dose escalation study to identify the maximum tolerated dose, which is defined as the highest dose with acceptable toxicity. An alternate approach is to jointly model toxicity and efficacy and allow dose finding to be directed by a pre-specified trade-off between efficacy and toxicity. With this goal in mind, several phase 1 designs have been proposed to jointly model toxicity and efficacy in phase… 

Figures and Tables from this paper


An adaptive dose‐finding design incorporating both toxicity and efficacy
An approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial is described, based on the flexible continuation‐ratio model, and uses straightforward optimal dose selection criteria.
Sequential designs for phase I clinical trials with late-onset toxicities.
A simulation study shows the method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2–4 years by the TITE‐CRM.
Bayesian Dose‐Finding in Phase I/II Clinical Trials Using Toxicity and Efficacy Odds Ratios
Under various scenarios, the new Bayesian design based on the toxicity–efficacy odds ratio trade‐offs exhibits good properties and treats most patients at the desirable dose levels.
Bayesian dose finding by jointly modelling toxicity and efficacy as time‐to‐event outcomes
A Bayesian adaptive phase I–II design that jointly models toxicity and efficacy as time‐to‐event outcomes and selects the target dose with a high probability, treats most patients at the desirable dose and potentially shortens the duration of a trial is proposed.
Continuous low-dose oral chemotherapy for adjuvant therapy of splenic hemangiosarcoma in dogs.
Continuous orally administered LDC may be an effective alternative to conventional high-dose chemotherapy for adjuvant therapy of dogs with HSA and that survival times would be comparable to those attained with conventional doxorubicin (DOX) chemotherapy.
Continual reassessment method: a practical design for phase 1 clinical trials in cancer.
A new approach to the design and analysis of Phase 1 clinical trials in cancer and a particularly simple model is looked at that enables the use of models whose only requirements are that locally they reasonably well approximate the true probability of toxic response.
Dose‐Finding Based on Efficacy–Toxicity Trade‐Offs
Computer simulations show that the new adaptive Bayesian method for dose‐finding in phase I/II clinical trials based on trade‐offs between the probabilities of treatment efficacy and toxicity has high probabilities of making correct decisions and treats most patients at doses with desirable efficacy–toxicity trade-offs.
Practical modifications to the time‐to‐event continual reassessment method for phase I cancer trials with fast patient accrual and late‐onset toxicities
An alternative approach useful in this setting by incorporating an accrual suspension rule is proposed and a simulation study designed based on a neuro‐oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE‐CRM while maintaining desirable design accuracy.
Safety evaluation of combination toceranib phosphate (Palladia®) and piroxicam in tumour-bearing dogs (excluding mast cell tumours): a phase I dose-finding study.
The combination of standard dosages of both drugs (toceranib phosphate and piroxicam) is generally safe and label-indicated treatment holidays and dose reductions may occasionally be required owing to gastrointestinal events.
Design and analysis of phase I clinical trials.
In Monte Carlo simulations, two two-stage designs are found to provide reduced bias in maximum likelihood estimation of the MTD in less than ideal dose-response settings and several designs to be nearly as conservative as the standard design in terms of the proportion of patients entered at higher dose levels.