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Novel Trial Designs are the Key to Expedited Drug Development, Expert Says

Shannon Connelly
Published Online:2:45 PM, Wed January 25, 2017

Evanthia Galanis, MD

The slow speed and high cost of developing new drugs has been a challenge for the field of oncology, and especially neuro-oncology, says Evanthia Galanis, MD.
 
Galanis recently chaired a session on clinical trials, where she discussed ways in which clinical trial design can be more efficient, and how the development of new drugs can ultimately be expedited. Galanis, professor of Oncology at the Mayo Clinic, and chair of the Neuro-Oncology Committee for Alliance for Clinical Trials in Oncology, discussed the issues that currently exist in clinical trial design, as well as how they can be addressed, during an interview with Targeted Oncology.
 
TARGETED ONCOLOGY:  You recently chaired a session on clinical trials. Can you give an overview of what you discussed during the session?
 
Galanis: This was a clinical trial session to think along the lines of how we can use novel trial designs to expedite drug development in oncology. This has been a challenge for oncology and, of course, for neuro-oncology as well. It has to do with the very slow speed and lack of efficiency when we try to develop novel therapeutics.
 
For example, for the average oncology drug, from the new drug application approval to marketing takes about 7 to 9 years and about $2.6 billion in cost. If someone thinks that only a small fraction of the drugs tested will end up being approved, that explains the huge cost of new drugs in oncology. We do think that with more innovative thinking in how we design these trials, the cost could be decreased and the speed of approval of new agents could be increased quite a bit.
 
TARGETED ONCOLOGY:  What are some ways that can be accomplished?
 
Galanis: [One method lies in] the clinical development with appropriate animal models. The bar should be very high in terms of which agents we test pre-clinically that make their way to clinical trials.
 
TARGETED ONCOLOGY:  How could the role and design of clinical trials be improved?
 
Galanis: We discussed phase I trial design, including accelerated titrated designs that can decrease the length of phase I trials. We discussed the importance of surgical studies to tell us if our drug gets to the brain tumor and incubates the target and also if it penetrates the adjacent blood brain. Blood-brain penetration is quite important for neuro-oncology drugs. 
 
A very important part of drug development is phase II trials, which is the intermediate step between the early development stages and the practice-changing, phase III trials. The reason they are important is because they effect the speed and the efficiency of new drug development in neuro-oncology. In addition, we use the data from phase II studies to design phase III trials. Strong data from phase II can determine the outcome of successful phase III trials. There are several designs that someone can use in the phase II context.
 
In general, single-arm trials have a limited role, especially if we look at endpoints such as progression-free survival and overall survival. We really have no way of knowing in a single-arm trial if the patient population is actually representative of an appropriate contemporary control.
 
However, if the drug has a high likelihood of resulting in a high response rate, then a single-arm trial can be quite appropriate. For example, with about 50% of drugs in oncology that were given the breakthrough drug designation since 2012, the approval was based on single-arm trials with objective response and duration of response being the primary endpoints.
 
Although it is somewhat challenging sometimes to measure response in brain tumors, this has been significantly changed and improved because of the development of response assessment systems, such as the Response Assessment in Neuro-oncology Criteria (RANO) system, which has improved our ability to measure response and progression. There is an international effort that is ongoing right now to standardize the MRI imaging protocols and use this standardized protocol in cooperative group trials and industry trials alike. Hopefully, down the road, also in clinical practice.
 
 
TARGETED ONCOLOGY:  How could the design of phase II trials specifically be improved?
 
Galanis: In the majority of trials in the phase II setting, we always want to have an appropriate control, so most designs in phase II need to be randomized, including some form of control there. The importance of the appropriate control arm was highlighted in 1 of the studies we saw presented in this meeting, the ACT4 trial with the use of rindopepimut (Rintega) in newly diagnosed glioblastoma (GBM). There, the treatment arm did extremely well, but that was still a negative study because the control arm did equally well.
 
We discussed a number of designs that can be applied in phase II including screening design, selection design—where you can select among multiple different promising compounds—as well as adaptive design, which will allow us to add arms, drop arms, possibly change and focus on a subgroup if a predictive biomarker has been identified, or even change the randomization, meaning learn as you go, in the conduct of the trial. This kind of design could allow us to answer multiple questions in 1 trial, and as a result, increase the efficiency by which we’re conducting clinical testing.
 
The time interval between phase II and phase III trials is quite long and adds quite a bit of drug development. An innovative way to address that is a hybrid form of design called a seamless phase II/III design where we use the phase II component as the learning stage and then we use the phase III component as the confirmatory stage.
 
The most efficient form of this design is the inferential seamless design, basically we’re able to use data for patients who are enrolled both in the phase II and in the phase III in order to conduct the final analysis and make inferences, so that creates a lot of savings in efficiency and in cost.
 
 
TARGETED ONCOLOGY:  Are these alternative trial designs currently being used?
 
Galanis: The Alliance for Clinical Trials in Oncology has tried to incorporate a lot of these designs in some of our ongoing trials. For example, a number of our studies have biomarker-driven designs, such as our CODEL clinical trial for patients with 1p19q co-deleted IDH-mutant oligodendrogliomas or our 501 trial to open for patients with BRAF-mutant craneofaringiomas.
 
Also, we have activated the first umbrella trial in neuro-oncology for meningioma patients where patients with meningiomas are undergoing a molecular characterization and then, depending on the molecular alteration—more common ones are NF2 alterations, AKT1 mutations, and smoothened mutations—patients are assigned to the appropriate drug corresponding to the target.
 
We are close to completing the first trial with a seamless phase II/III design in oncology, which is a phase II/III trial testing the addition of veliparib, a PARP inhibitor, to the standard of care, temozolomide (Temodar), followed by temozolomide in patients with newly diagnosed GBM and methylated tumors. Only MGMT-methylated patients are eligible, and then we’re using this seamless phase II/III design. We’re three-fourths of [the way through] the trial right now, so we’re going to be able to essentially complete the study in about 3.5 years from activation, while if we were to follow sequential phase II followed by phase III design in this context, it would be more of a 7- to 8-year process.

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