Abstract
Background
In this article we describe the methodology of the time-to-event continual reassessment method in the presence of partial orders (PO-TITE-CRM) and the process of implementing this trial design into a phase I trial in head and neck cancer called ADePT-DDR. The ADePT-DDR trial aims to find the maximum tolerated dose of an ATR inhibitor given in conjunction with radiotherapy in patients with head and neck squamous cell carcinoma.
Methods
The PO-TITE-CRM is a phase I trial design that builds upon the time-to-event continual reassessment method (TITE-CRM) to allow for the presence of partial ordering of doses. Partial orders occur in the case where the monotonicity assumption does not hold and the ordering of doses in terms of toxicity is not fully known.
Results
We arrived at a parameterisation of the design which performed well over a range of scenarios. Results from simulations were used iteratively to determine the best parameterisation of the design and we present the final set of simulations. We provide details on the methodology as well as insight into how it is applied to the trial.
Conclusions
Whilst being a very efficient design we highlight some of the difficulties and challenges that come with implementing such a design. As the issue of partial ordering may become more frequent due to the increasing investigations of combination therapies we believe this account will be beneficial to those wishing to implement a design with partial orders.
Trial registration
ADePT-DDR was added to the European Clinical Trials Database (EudraCT number: 2020-001034-35) on 2020-08-07.
In this article we describe the methodology of the time-to-event continual reassessment method in the presence of partial orders (PO-TITE-CRM) and the process of implementing this trial design into a phase I trial in head and neck cancer called ADePT-DDR. The ADePT-DDR trial aims to find the maximum tolerated dose of an ATR inhibitor given in conjunction with radiotherapy in patients with head and neck squamous cell carcinoma.
Methods
The PO-TITE-CRM is a phase I trial design that builds upon the time-to-event continual reassessment method (TITE-CRM) to allow for the presence of partial ordering of doses. Partial orders occur in the case where the monotonicity assumption does not hold and the ordering of doses in terms of toxicity is not fully known.
Results
We arrived at a parameterisation of the design which performed well over a range of scenarios. Results from simulations were used iteratively to determine the best parameterisation of the design and we present the final set of simulations. We provide details on the methodology as well as insight into how it is applied to the trial.
Conclusions
Whilst being a very efficient design we highlight some of the difficulties and challenges that come with implementing such a design. As the issue of partial ordering may become more frequent due to the increasing investigations of combination therapies we believe this account will be beneficial to those wishing to implement a design with partial orders.
Trial registration
ADePT-DDR was added to the European Clinical Trials Database (EudraCT number: 2020-001034-35) on 2020-08-07.
| Original language | English |
|---|---|
| Article number | 11 |
| Journal | BMC Medical Research Methodology |
| Volume | 24 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 13 Jan 2024 |
Bibliographical note
The ADePT-DDR trial is funded by AstraZeneca. This research was conducted with support from AstraZeneca UK Limited.Keywords
- PO-TITE-CRM
- Partial orders
- Toxicity
- Dose-finding
- Phase I trial
- ADePT-DDR
- Monotonicity assumption
