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
Further reading:
- 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.
1 comment:
the proper reference to references 1,2,and 4 above is Iasonos and O’Quigley
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