Clinical trials are conducted in a series of steps, called phases - each phase is designed to answer a separate research question. In Phase I studies, Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase I trials are usually conducted in healthy volunteers, however, phase I trials are often conducted in patients for 1) Trials in life-threatening diseases (such as cancer, AIDS); 2) clinical trials with human plasma derived products; 3) clinical trials with some biological products; 3) clinical trials with gene-therapy
Many phase I studies are designed as a dose escalation study. In previous articles, I have discussed the Phase I Dose Escalation Study Design: "3 + 3 Design" and Alternative phase I dose escalation study designs: CRM, BLRM, mTPI, and PGDE. The purpose of these dose escalation studies is to find the maximum tolerable dose (MTD). However, the efficacy signal can also be detected/assessed.
In a recent issue in New England Journal of Medicine, Prowell et al published an article titled “Seamless Oncology-Drug Development” and discussed the suddenly popular study design so called ‘dose cohort expansion study’. The study on pembrolizumab or MK-3475 or Keytruda (a programmed cell death 1 receptor) by Merck was mentioned as the example.
The study was initially designed as a typical dose escalation study with a title “Phase I Study of Single Agent MK-3475 in Patients With Solid Tumors”. The anticipated number of subjects was 32. “When impressive response rates and durations of response were observed early in the trial, particularly in patients with metastatic melanoma or non–small-cell lung cancer, the sample size was rapidly increased. Cohorts were added to assess efficacy in these two patient populations and to evaluate alternative dosing regimens and candidate predictive biomarkers — a move that resulted in the enrollment of more than 1200 patients in the trial”
This phase I study is still active, but not recruiting participants at this point. The latest description on clinicaltrials.gov is so much different from the original study design. The official title of the study has been revised to “Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma”. The change history documented on clinicaltrials.gov indicated 60 updates. One of the FDA review documents stated that the protocol was amended 50 times and counting.
While the protocol is still staged as a phase I study, many of the sub-studies have been added to this phase I study protocol. The study design is way beyond the initial dose escalation. The purpose of the study has been shifted to demonstrate the efficacy with an appropriate dose level. Within some added cohorts, the control group was added and subjects were randomly assigned. Essentially this is a combined phase I/II studies with multiple sub-studies. If it is designed in traditional phased clinical trial approach, this one study will have to be split into multiple phase I and phase II studies.
With portion of the results from this phase I study, Merck has obtained the approval from FDA initially for Advanced Melanoma, and last October for Non-small cell lung carcinoma. FDA review documents for its approval for advanced Melanoma have been posted on FDA’s website and the review documents for its approval for non-small cell lung carcinoma should be posted soon.
Cohort expansion design has now been used by many other study sponsors. We can easily see these studies with cohort expansion design from the clinicaltrials.gov website. In cohort expansion study, the decision on which cohort to add and how many subjects to expand depends on the results from the previous cohorts. However, it is very different from the adaptive design where the adaptation rules are pre-specified. In cohort expansion study, the changes to the study design are all post-hoc.
Cohort expansion study can be replaced with multiple phase I and phase II studies. However, keeping the study under the same protocol (but with many protocol amendments) will probably still save time and budget in study conduct, patient recruitment, IRB/EC submissions, and regulatory submissions. In a very competitive environment for oncology drug development, the time has the ultimate importance.
Cohort expansion design becomes a viable approach in drug development perhaps due to following special circumstances:
- Its application in oncology studies where the phase I study is directly in patients, not healthy volunteers
- The study is open-label, not blinded
- In clinical trials for diseases that meet “Expedited Programs for Serious Conditions” defined in FDA’s guidance
- In the drug with breakthrough therapy designation
- Lasonos and O’Quigley (2014) Dose expansion cohorts in Phase I Trials
- Lasonos A and O’Quigley Early phase clinical trials—are dose expansion cohorts needed? Nat Rev Clin Oncol. 2015 November; 12(11): 626–628.
- Boonstra et al (2015) A Statistical Evaluation of Dose Expansion Cohorts in Phase I Clinical Trials
- Lasonos and O’Quigley (2012) Design Considerations for Dose-Expansion Cohorts in Phase I Trials
- Sanborn et al (2013) A Phase 1 Dose-escalation and Cohort Expansion Study of Lirilumab (Anti-KIR; BMS-986015) Administered in Combination With Nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in Patients With Advanced Refractory Solid Tumors
- Robert C et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17.
- Ribas A et al. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA. 2016 Apr 19;315(15):1600-9.
- Garon EB et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28.
- Hamid O et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44.