During phase 1 clinical trials, it is essential to establish safe and recommended dosages of the study drug or treatment. To determine this, dose escalation methods are used to examine the most tolerable dosage of the drug in patients early on in the trial. Read about the stages of clinical trials.
The objective of dose escalation is to prevent the trial from administering too many subtherapeutic doses that do not achieve the intended effect, while ensuring patients are not exposed to unsafe levels of the drug.
What is dose escalation?
Dose escalation trials use increased level drug doses to examine the maximum tolerated dose (MTD) of a study drug. Dose escalation usually takes place across phase 1 clinical trials, where researchers establish the safest drug dosage level to administer to patients throughout the remaining trial phases.
Establishing the maximum tolerated dose early on in the trial reduces the potential risks to patients as the trial progresses. This is particularly important for trials that test on healthy volunteer groups during phase 1 research, and then proceed with patient group testing in phase 2.
The dose escalation process is thorough and detailed. The decision to increase drug dosage is made by key investigators and sponsors based on findings from sound data. This decision places volunteers and patients on higher dosages, making it vital for this safety decision to be based on accurate information.
Dose escalation case study
We recently delivered an effective dose escalation clinical trial for a sponsor seeking to ensure first-in-patient (FIP) study success in a highly competitive oncology field.
The trial tested a new study drug for patients with relapsed non-hodgkin’s lymphoma (NHL) and relapsed chronic lymphocytic leukaemia (CLL). Using dose escalation study design, our investigators tested the maximum tolerated dose of the test drug in trial patients.
See the full dose escalation study details in our relapsed NHL and CLL case study report.
Objectives
Our main objective was to investigate the safety and tolerability of the study drug in patients with relapsed NHL and relapsed CLL. Our aim was to obtain preliminary data on the antitumour efficacy of the study drug given as monotherapy dose escalation to relapsed NHL and CLL patients.
Challenges
As a highly competitive field of research, there were several potential challenges faced throughout the study. It was vital that study sites were fully committed to the research, with no competing projects taking place or being planned in conjunction with this study.
To ensure that the research ran smoothly, the dose escalation study was designed to fulfil the scientific and regulatory objectives without being overly complex. This avoided the risk of discouraging investigators and patients from taking part.
In dose escalation research, it is vital that each decision to increase the drug dosage is backed by sound data. Our agile study design and data management allowed for dose escalation decisions to proceed rapidly and without bias. This reduced the risk of competition among centres for slots in the dose escalation cohorts as a result of favourable IMP results.
Study design solutions
To test the tolerability of the study drug, we devised a dose escalation trial design.
Doses of the study drug were administered to patients as monotherapy, giving escalating oral doses in order to examine the safety, tolerability and efficacy of increased dosage levels.
We examined peripheral blood lymphocytosis and recovery to assess the efficacy of the study drug with increased dosages.
The research required a minimum enrolment of 42 patients. To meet this requirement, we worked closely with the sponsor to ensure the study was as patient friendly as possible.
The study design was optimised to increase investigator and patient participation through the following methods:
- Visiting each potential study site to ensure key personnel were engaged with the project and momentum was maintained.
- Monitoring the number of enrolled patients across each site and within each cohort and prioritising sites that had not enrolled in particular cohorts.
- Ensuring close communication with the sponsor to optimise IMP management and cost-effectiveness.
- Ordering the next dosage up from the approved dose escalation to ensure the next level was rapidly available when required
Trial outcome
Thanks to an agile and efficient study design, the therapeutic principle and escalation dose approvals were established rapidly.
This allowed the sponsor to communicate results with scientific and business communities much earlier than originally anticipated, and with a much larger dataset comprising 90 patients rather than the minimum requirement of 42 patients.
These results led to highly favourable commercial development outcomes for the sponsor.