How to Accelerate Development in Novel & Advanced Oncology Therapies - From the Starting Line
Early-phase oncology clinical trial design is evolving rapidly offering biotechs new opportunities to accelerate their clinical development. To support biotechs navigate this changing landscape, Novotech and Endpoints News recently assembled an expert panel to share their early phase oncology trial design insights.
“If you don’t get it right in the beginning if you’re a small biotech, it’s hard to go back and start over,” said Dr Patricia Mucci LoRusso, the Director of the Early Phase Clinical Trials Program and Associate Center Director, Experimental Therapeutics of the Yale Cancer Center in New Haven, Connecticut.
She said trials have become much more complex, “and the demands and the data points have become significantly greater”.
“The number of exploratory endpoints has really exploded in many of these trials relative to what we used to see several years ago.”
New oncology study designs have also been recently recommended by the FDA. The Oncology Center of Excellence (OCE) Project Optimus is an initiative to reform the dose optimization and dose selection paradigm in oncology drug development.
“Too often, the current paradigm for dose selection—based on cytotoxic chemotherapeutics—leads to doses and schedules of molecularly targeted therapies that are inadequately characterized before initiating registration trials,” according to the FDA.
Dr. LoRusso said: “Project Optimus is trying to identify what the right dose is instead of giving too much of a dose because it’s the maximum tolerated dose. Perhaps less of a dose that can allow the patient to maintain on that agent more chronically without dose interruptions or dose reductions is one of the recent driving forces within the FDA guidelines. Trying to maximize efficacy but minimize toxicity.”
“There’s been a big push for that, not only by the FDA, but advocacy groups have pushed for it in hopes that we’re no longer pushing a drug so high that you have to have so many interruptions that it may actually, in the long run, be less efficacious.”
“Also, there’s a lot more input into more novel biostatistical designs.”
“Bayesian optimal interval (BOIN) designs are becoming more commonplace in early phase trials.”
“I think the way forward is going to be away from 3+3 and more towards these designs so that we can maximize the data that we’re obtaining from each individual patient so we can get it right as early as possible within the context of a Phase 1 trial.”
“It’s a well-known fact, especially with targeted drugs, that we would get a recommended Phase 2 dose, and 45 to 50% of the time conservatively it’s been shown that that dose is not the right dose in Phase 3 and that’s a very expensive error.”
“9% of Phase 3 trials had historically been aborted because the wrong dose was chosen to advance forward.”
Dr. Vishal Navani, the Staff Medical Oncologist and Professor of the Tom Baker Cancer Centre, University of Calgary in Calgary said there are so many endpoints needed and data required from these early phase trials that “using a Bayesian approach or a BOIN approach gets the most out of each patient’s kind voluntary time that they spend with us on a trial”.
“I like model-assisted designs like BOIN because they’re flexible. Let’s say, for example, you have a bispecific trial and you’re worried about a specific toxicity like cytokine release. Well, you can set a dose-limiting toxicity rate of 10%, let’s say, for argument’s sake with BOIN. Whereas using a rule-based design like 3+3, you can’t really do that,” said Dr Navani.
“If you use a time-to-event point, it can capture toxicities throughout the entire time the patient’s on therapy, rather than just waiting for one experience of dose domain toxicity.“
Michele Gerber, the Chief Medical Officer at Myeloid Therapeutics in Cambridge, USA said Myeloid Therapeutics has incorporated Bayesian designs in their drug development programs.
“The 3+3 design was really designed for chemotherapy and for determining the maximum tolerated dose. With gene and immune targeted drugs, we really need to find out the optimal doses which may not be at the maximum tolerated dose,” she said.
“Bayesian designs were the best way forward for our project. We believe that they improve the precision of the safety profile and allow earlier information on the therapeutic index.”
“There’s really two main Bayesian designs, one on model-based and the other model-assisted design. Which one you choose is dependent on operational feasibility, including the expertise and infrastructure with the model-based designs being much more difficult to implement. The model-assisted designs include the BOIN design. That’s what we’ve chosen to use in our in vivo program.”
In addition to trial design options, geographic advantages can also accelerate early phase oncology trials.
Prof Jayesh Desai, Medical Oncologist and Clinical Research Head, Early Drug Development at the Peter MacCallum Cancer Centre in Melbourne, Australia said Australia offers rapid activation timelines.
He said in Australia, we have excellent alignment between investigators’ sites and our regulatory agencies and ethics committees. “It’s been an environment where we’ve managed to get things going very quickly. Our activation timelines are very good and I think that’s been attractive for the industry.”
“I’d like to hope that industry comes to Australia because of the quality of the investigators and the sites, not just because we do things quickly.”
“The strategy of beginning a first time in human trial in Australia and then, for example, moving that to the US, as you move through dose escalation or even towards the latter parts of dose escalation. That’s something that we’ve done many, many times.”
Kedan Lin, the Senior Vice President at Harbour BioMed in South San Francisco, USA said her company had also opened sites in Australia.
Kedan Lin said Australia offers “a very quick start and the data quality is excellent”.
“We can actually leverage the data we obtain from Australia to open up the site trials in the US or in China or somewhere else.”
She said Australia’s population diversity can also help meet FDA trial diversity requirements.
She said CROs like Novotech have a very strong presence in Australia. “They help the sponsor get to the key decision point very quickly.”
“We have had a wonderful experience in Australia.”
Michele Gerber said her company was initiating the trial for their invivo program in Australia. “We have decided to go there first and foremost because of the excellent medical system that exists there and the very strong Phase 1 units. Also, we are using a lot of academics to support our translational program. In addition, the regulatory pathway is very well defined. It’s easy to navigate and very efficient.”
“Lastly, very importantly for a small biotech company, the trials are less expensive than in the US, and that supports our needs to really conserve funds.”
Dr. LoRusso said: “I can honestly tell you that I’ve really enjoyed working with Australian sites and outstanding investigators.”
Dr. Navani addressed the issue of protocols and enrollment barriers –“There’s been some recent FDA guidance on improving eligibility and minority representation in trials and expanding access to trials so that they already reflect the populations that the end drug may serve.”
“I think that sponsors need to work hard in helping a broader panel of potential patients recruit onto trials and deal with the language, communication, health literacy barriers that may prevent the patient from enrolling onto an early phase trial.”
“I also think we need to think as a field more broadly about expanding inclusion criteria, especially in the early phase setting.”
Contact Novotech for more information about optimal trial design for clinical development acceleration here.
View the expert panel video here.