The nonprofit Friends of Cancer Research (Friends) held its annual meeting exploring innovative ways to streamline clinical trials safely to bring effective therapies to patients earlier. Friends has strongly supported faster approval of effective cancer drugs, including the Breakthrough Therapy designation at the U.S. FDA.
The annual meeting was held during the government shutdown. Friends Founder and Chair Ellen V. Sigal, PhD, said colleagues from federal agencies such as the FDA would be missed. But, she said, “We must remain steadfast in our support for science. Patients can’t wait.”
Friends released three new white papers, each addressing specific strategies to streamline the cancer clinical trial process. They are Seamless Clinical Trial Designs in Rare Cancers: Leveraging Operational and Adaptive Strategies to Accelerate Drug Development; Trial Designs for Combination Drug Development; and Control Arm Selection for Multi-Regional Clinical Trials.
Rare cancers pose challenges for cancer drug development, since small, heterogeneous patient populations limit the feasibility of randomized controlled clinical trials. A seamless, adaptive trial, rather than the traditional, sequential phase I (safety and dose finding), phase II (initial efficacy), phase III (comparison to standard of care) design with pauses in between, can accelerate rare cancer drug development for small patient populations with complex biology, said Allen S. Melemed, MD, Chief Medical Officer of Chimerix and moderator of the panel on the first white paper. A seamless trial, as defined in the white paper, is “a clinical trial integrating multiple, sequential stages of drug development—such as dose escalation, dosage optimization, cohort expansion, and efficacy assessment—within a single framework.” In this integrated approach, early, meaningful endpoints maximize the insights gained from each patient.
Patients with rare cancers don’t have much time, so it makes sense to put phase I and phase II together using the same protocol, said Misha Mehta, PhD, a Friends advocate who is Senior Director of Research for the Pediatric Brain Tumor Foundation. “You’re saving money and resources,” said Mehta, who lost her young son Neev to a rare brain cancer. “Seamless trials make so much sense because they combine safety and dosing in one continuous process,” she added.
What is also necessary for a seamless, adaptive trial is a robust institutional infrastructure, said Ying Yuan, PhD, Professor and Chair of the Department of Biostatistics at the University of Texas MD Anderson Cancer Center. Yuan noted that computer simulations can be helpful when thinking about all the possible scenarios for a seamless, adaptive trial.
Speakers discussing the second white paper emphasized that the pace of oncology drug development is accelerating rapidly, with a growing emphasis on the use of combination therapies to improve outcomes. However, introducing additional drugs into a regimen can increase toxicity, making it important to be sure that each drug is contributing to the patient’s therapeutic benefit. This paper explores flexible trial design options to study the contribution of effect (COE) or the impact of each individual drug in a combination therapy. The white paper notes that using early evidence of COE in one cancer type can support streamlined development across other cancer types, especially for rare cancers.
Combination trial designs are being increasingly used in drug development, said Gideon Blumenthal, MD, Vice President for Global Clinical Development in Oncology at Merck & Co. Results of such trials can be synergistic, additive, or unfavorable, said Blumenthal.
With more agents used, there is more toxicity. As a result, it is important to identify the toxicity for each individual patient in a combination trial, said Blumenthal. “Safety is a concern early on and throughout,” he said.
Blumenthal stressed that it is important to bring these innovative, adaptive cancer trials to community settings as much as possible, since about 80% of cancer patients are treated in the community. If a combination treatment is approved, he noted, it is likely that most patients will receive treatment with it in community facilities.
Patients entering these trials need very clear communication about their risks and potential benefits, as well as crystal-clear consent documents, stressed Carol Vallett, a Friends advisory advocate and breast cancer survivor. She noted that she lives in Vermont, a state where people often must drive a long way for medical care. She urged investigators to try to reduce the burden and complexity of adaptive trials for enrolled patients as much as possible.
Speakers on the panel featuring the third white paper said that global multi-regional clinical trials (MRCTs) in oncology can speed up patient access to new cancer therapies, improve the diversity and generalizability of clinical data, and enable a more efficient review process across regions. However, a major challenge in the design of such trials is choosing an appropriate standard of care (SOC) comparator, since this can vary widely across regions due to “differences in regulatory approvals, clinical guidelines, real-world practice, access, and reimbursement.”
“Control arms should reflect the current standard of care,” but a changing SOC puts pressure on drug sponsors, said Harpreet Singh, MD, Chief Medical Officer at Precision for Medicine, a clinical research organization, and moderator of this session. She said what is needed for MRCTs is a carefully guided process for comparator selection.
Most patients don’t know that SOC can vary by country, said Kristin McJunkins, MEd, a Friends advisory advocate and melanoma survivor. Therefore, she said, researchers have to be “very transparent” in communication about an MRCT trial.
Not anticipating change is “the worst thing” one can do when embarking on a clinical trial, said Sumithra Mandrekar, PhD, Professor of Biostatistical Oncology at the Mayo Clinic. She said the possible different scenarios for an MRCT trial need to be planned out in advance.
Patient trust is especially important in MRCTs, said Raymond Osarogiagbon, MBBS, FACP, Director of the Multidisciplinary Thoracic Oncology Program and the Thoracic Oncology Research Group at Baptist Cancer Center. “Patients trust us; we have to earn that trust,” he said. While rapid-cycle drug development is a good thing, “We have to constantly remember that the patient is at the center,” he emphasized.
Peggy Eastman is a contributing writer.