To address the shortfall of new oncology drugs developed for pediatric cancer patients, the Friends of Cancer Research (FOCR) convened a forum with invited speakers in Washington, D.C. Speakers discussed the feasibility of master trial platforms for early phase studies of multiple molecules concurrently across a range of pediatric cancer types, as well as prioritization criteria to help identify the most promising molecules to take forward from a master trial protocol into pivotal studies.
“This is a really important topic,” said FOCR Chairperson and Founder Ellen V. Sigal, PhD. “Our goal is simple: we have to help children.” The FOCR distributed two discussion papers on master trial protocols at the forum.
While cancer is the leading disease-related cause of death for children ages 1-19, it is comparatively rare, according to the American Cancer Society (ACS). In 2016, ACS estimates put the number of new U.S. cancer cases at 10,380 for children ages 0-14, and at 4,280 for adolescents ages 15-19.
Oncology pediatric drug development faces a number of challenges, said speakers. “The field is changing and the populations are increasingly smaller,” said Peter Adamson, MD, Chair of the Children’s Oncology Group; Professor of Pediatrics and Pharmacology at the Perelman School of Medicine of the University of Pennsylvania; and holder of the Alan R. Cohen Endowed Chair in Pediatrics at The Children’s Hospital of Philadelphia. Because there are smaller numbers of patients, it is difficult to attract research investors looking for a return on their investment, noted Mark Fleury, PhD, Principal for Policy Development and Emerging Science for the ACS Cancer Action Network.
Thus, in pediatric drug development, there is often crossover research from adult drug development, Fleury explained. But he noted that childhood cancers are often biologically different from cancers with the same name in adults, indicating that childhood-specific cancer research is needed. For example, acute lymphoblastic leukemia genetic subtypes differ between adults and children, so the therapies often must be tailored for each different subtype.
In addition, Fleury said, side effects from pediatric oncology treatment can be significant, because they occur during a vulnerable period of a child’s growth and development. And since children’s survival times following therapies will be longer, they are subject to late effects of treatment, some of them life-threatening. It also can be difficult to recruit enough children into a clinical trial, according to the ACS, either due to a small number of diagnosed patients or to competition between different research projects for the same pediatric cancer patients.
“From my perspective, this is the biggest problem in cancer,” Gregory Reaman, MD, Associate Director for Oncology Sciences in the Office of Hematology and Oncology Products at the FDA, said of oncology drug development for children. Reaman thanked the FOCR for holding the forum, and noted that the Pediatric Subcommittee of the FDA’s Oncologic Drugs Advisory Committee has stated that a pediatric oncology drug development program should be designated a priority. Reaman agreed with Fleury that most pediatric drug research aims to leverage adult drug discovery, and said, “I think we have to do a better job of leveraging that discovery.”
Making pediatric cancer drug development even more challenging is the fact that childhood cancers generally have lower mutation rates than adult cancers, said Nita L. Seibel, MD, Head of Pediatric Solid Tumor Therapeutics in the Clinical Investigations Branch, Cancer Therapy and Evaluation Program, Division of Cancer Treatment and Diagnosis, NCI. Seibel said NCI plans to open its adult MATCH (Molecular Analysis for Therapy Choice) trial to children and adolescents; this trial is purely based on the targeted abnormality, not on histology. She said it is anticipated that just 10 percent of children will have a mutation that can be matched to a targeted drug.
What is really needed to advance pediatric cancer drug development is a “magic overlap” that includes pediatric cancer patients with actionable mutations, putting these patients on the right trial and the availability of a matched drug for those identified mutations, said Katherine Janeway, MD, MMSc, Senior Attending Physician in Pediatric Hematology-Oncology at Dana-Farber Cancer Institute and Boston Children’s Hospital and an Assistant Professor of Pediatrics at Harvard Medical School.
Janeway discussed the TAPUR (Targeted Agent and Profiling Utilization Registry) trial of ASCO; she is Chair-Elect of the ASCO Cancer Research Committee and is on the TAPUR Steering Committee. She said ASCO is considering broadening eligibility criteria for enrollment in TAPUR and looking at lowering the age of participation in TAPUR to 12. Janeway said ASCO wants to ensure TAPUR really is a real-world study, representative of oncology practice, and noted: “It is anticipated that the number of children who benefit from a precision oncology approach will increase.”
Pediatric oncology is “well-poised” for adaptive trial designs under the umbrella of an overarching multi-sponsor master trial platform for phase I/II drugs, said Reaman. Such an overarching master protocol might shorten the development timeline, lead to more efficient dose finding studies, and lead to innovative trial designs. He stressed the need to maximize regulatory authority, and noted that the Pediatric Research Equity Act (PREA), which requires pediatric assessment of new drugs (but not orphan drugs) and the Best Pharmaceuticals for Children Act (BPCA) offer avenues to boost pediatric cancer drug development. Reaman said the authority of PREA might be able to be expanded, and noted there is a BPCA pediatric working group that holds quarterly meetings with representatives of academia to discuss promising new agents for pediatric cancer evaluation.
While master trial protocols offer opportunities for efficiency, they do present unique challenges, such as providing the necessary training and education to trial site participants to ensure uniformity in data collection and patient enrollment. An additional consideration is whether a master protocol could delay or restrict access to the investigative agent for alternative pediatric proposals that arise.
Since many pediatric cancers occur in very small numbers of children, Reaman suggested that the Orphan Drug Act, passed in 1983, offers a promising path for pediatric cancer drug development that is not taken often enough. “In my opinion, it is not adequately taken advantage of for pediatric cancers,” said Reaman. “What could be a bigger orphan population than children?” he asked, pointing out that the Orphan Drug Act offers “incredible financial incentives” to companies to develop drugs for small numbers of patients (under 200,000).
Among the discussion topics raised at the FOCR forum are these:
- What is the optimal trial design for mechanism of action/target-based multi-agent, multi-sponsor platform trials?
- What is the appropriate timing to consider inclusion of a drug in a master protocol?
- What is the appropriate biomarker and patient selection strategy (for example, all-comer approach vs. genetic signature)?
- When might master protocols not be appropriate (for example, agents at different clinical or development phases)?
- Is there potential for accelerated approval from the phase II portion of the signal-seeking master protocol trial?
- What are the licensing considerations and timing of registration studies?
- What is the most appropriate method for molecular prioritization (for example, prevalence of eligible patients, mechanistic rationale, safety profile)?
- Who oversees the process?
Speakers said the development of pediatric master trial protocols will require the cooperation, collaboration, and engagement of investigators, cooperative groups, industry, institutional review boards, and regulatory agencies to overcome barriers that could impede pediatric cancer drug development. “The need to collaborate between companies is increasing,” said Adamson. “Collaboration requires a culture change,” added Sigal. “I would say it’s probably the biggest barrier.”
Collaboration is urgently needed because “the limitations on treatments and options are just terrible,” said Raymond Rodriguez-Torres, MMgt, CEO of ALC Home Health and Chairman of Live Like Bella, the childhood cancer foundation he started in memory of his preschool-aged daughter, who died from stage IV alveolar rhabdomyosarcoma. Rodriguez-Torres said pediatric master protocols are very important to maximize resources, and that with collaboration they could provide the potential for a valuable repository of genetic information.
In considering collaboration, “Globalization is needed,” stressed Gilles Vassal, MD, PhD, Professor of Oncology at University Paris XI and Head of Clinical Research at the Institut Gustave Roussy. “If companies work together with us, we can really make some progress.”