1. Eastman, Peggy

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A new FDA legislative mechanism holds the promise of filling a well-known innovation gap in pediatric cancer drug development, according to speakers at a meeting on molecularly targeted cancer therapies for children and adults hosted by the Friends of Cancer Research (FOCR) in Washington, D.C. The organization produced a background paper on the topic (not a consensus document) with contributions from many individuals to explore the path forward in accelerating such development.

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"There's nothing more devastating than a child not getting the right treatment," noted FOCR founder and Chair Ellen V. Sigal, PhD, in opening the meeting. For this reason, she considered the meeting's topic "extraordinarily important."


The new FDA legislative mechanism puts teeth into discovering effective new drugs for children with cancer. Specifically, the RACE for Children Act, Title V of the FDA Reauthorization Act of 2017, amended the Pediatric Research Equity Act (PREA) by mandating early pediatric evaluation of new drugs intended for adults with cancer. Recognizing the major contribution of molecularly targeted agents to precision oncology, Title V specifies that FDA may require by statute early pediatric investigations of molecularly targeted cancer drugs. Before this new amendment, PREA had not been considered an effective mechanism for developing drugs for pediatric cancers.


Title V directs the FDA, in collaboration with the NCI, to establish, publish, and regularly update a list of molecular targets the agency considers may be relevant enough to the growth or progression of pediatric cancers to trigger the requirement for a pediatric investigation. The amended law also directs the FDA to hold an initial public meeting for stakeholders and convene future public meetings to undergird the establishment of the molecular targets list. The FOCR background paper presents a framework of factors to guide the establishment, updating, and application of the molecular targets list.


Pediatric cancers differ from adult cancers in their etiology and biology, said Gregory Reaman, MD, FDA's Associate Director for Oncology Sciences at the Center for Drug Evaluation Research (CDER), and Associate Director for Pediatric Oncology at the FDA's Oncology Center of Excellence. Historically, treatment of children with cancer has been shaped by off-label use of adult drugs, and the diagnosis of cancer in children, especially metastatic cancer, "has been suboptimal," added Reaman, inaugural and Immediate Past Chair of the Children's Oncology Group (COG).


The new legislation will help fill the void in pediatric cancer drug development, Reaman stressed. "We must focus on the intent of this legislation," he said, which is to trigger early pediatric investigations of agents with promising signals. "Ideally, defining a profound effect is what we'd all like to see."


Asked by Oncology Times if the RACE for Children Act will truly be a motivator for pharmaceutical companies-given that cancers in children are rare-Reaman said, "Absolutely." He noted that, for example, today pharmaceutical companies are developing drugs for adult cancers with smaller and smaller subsets of patients.


Molecular Targets

Much of the discussion at the FOCR meeting-and the contents of the background paper-focused on development of the molecular targets list mandated by the new FDA legislation. The FOCR background paper was meant to serve as a framework, not as a checklist, emphasized Malcolm A. Smith, MD, PhD, NCI's Associate Branch Chief for Pediatric Oncology, Cancer Therapy Evaluation Program, where he serves as the Program Director and primary NCI liaison to childhood cancer researchers in COG. He noted that, while most childhood cancers have a low mutational burden, certain targets may be relevant in pediatric oncology.


The FOCR background paper includes a table which lists factors for consideration in determining whether molecular targets are substantially relevant in the growth or progression of pediatric cancer. These factors include the following, among others:


* the target has been identified in at least one case of a pediatric cancer;


* the gene abnormality in a gene abnormality target class has been identified in at least one case of a pediatric cancer;


* the target in a cancer cell lineage target class is intrinsically and differentially expressed in the cancer of interest compared to normal site-specific tissues;


* non-clinical evidence shows relevant in vitro or in vivo activity; and


* biomarkers that predict responses to target modulation may be useful in the selection of appropriate pediatric study populations.



The FOCR paper states, "Because of the importance of non-clinical evaluation in determining relevance of molecular targets, every effort should be made to ensure sponsors expedite early non-clinical investigation, which could be in collaboration with academic research teams with pediatric expertise in non-clinical testing. As with any clinical study, investigations in pediatric patients must be scientific and ethically justified, taking into consideration the prospect of direct benefit to individual children and adolescents with cancer."


The paper also stresses that if a molecular target is considered to be substantially relevant to the growth or progression of pediatric cancer, but its toxicity profile is too adverse, "conducting a pediatric investigation using this agent may not be justified and further development may be precluded."


The list of molecular targets with potential relevance to pediatric cancer patients should not be restrictive, but should enhance broad new drug development, emphasized Peter C. Adamson, MD, Chair of COG, Professor of Pediatrics and Pharmacology at the Perelman School of Medicine at the University of Pennsylvania, and the Alan R. Cohen Endowed Chair in Pediatrics at the Children's Hospital of Philadelphia. "My worry is that the list could take on a negative connotation," said Adamson, who serves on the National Cancer Advisory Board and was a member of the Blue Ribbon Panel for Vice President Joe Biden's National Cancer Moonshot Initiative.


He said his hope for the new legislation is "not to have an onerous new requirement," but rather to have a tool that serves as a catalyst for pharmaceutical companies to accelerate pediatric cancer drug research and development. COG is sponsoring Project:EveryChild, which aims to ensure that every childhood cancer, no matter how rare, will be studied by the more than 200 pediatric programs of COG.


In July 2017, NCI and COG announced the opening of enrollment for a unique clinical trial of precision medicine for children: NCI-COG Pediatric Molecular Analysis for Therapy Choice (Pediatric MATCH). This U.S. trial will explore whether targeted therapies can be effective for children and adolescents with solid tumors that harbor specific genetic mutations and have progressed during or after standard therapy. Pediatric MATCH will use a single sequencing test to screen for many molecular abnormalities at once, and will incorporate study drugs that target predefined sets of genetic mutations.


Expert Thoughts

Like Adamson, Nancy Goodman, Executive Director of Kids v Cancer and the lead advocate for the RACE for Children Act, said she has some concerns about the molecular targets list. She said she fears that the framework suggested by the FOCR background paper could deter or delay FDA from assessing molecular targets not on the list. But, "we don't intend to be held hostage by the list," stressed Martha Donoghue, MD, the FDA's clinical lead for Gastrointestinal Cancers Team, Division of Oncology Products 2, Office of Hematology and Oncology Products, CDER. She stressed that "the list should cast a wide net." Added Reamer, "This list...shouldn't really drive what we do with this legislation."


Given the increasing discovery of new molecular targets in oncology, the list is likely to keep expanding and will need frequent review and updating, said several speakers. "If we were having this meeting 10 years ago," the range of molecular targets that would have been discussed would have been much more limited, noted Peter Ho, MD, PhD, Chief Medical Officer for Boston Pharmaceuticals. He stressed that the new Title V legislation provides welcome opportunities for new target development, citing public meeting workshops for all stakeholders, a transparent nomination mechanism for molecular targets during or before meetings of the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee, and a process whereby clinical investigators or drug sponsors can request a meeting with the FDA to discuss new scientific data related to a new or existing molecular target.


FOCR meeting participants agreed there are questions that need to be further addressed for the new RACE for Children Act to be fully implemented. Some of these questions, which were posed in the FOCR background paper, include the following.


1. Should the term "molecular target" be used only for a molecule that already has an agent that modulates its activity and that is either fully developed or in the process of development?


2. What is considered an optimal level of evidence required for the factors presented in the background paper's framework that may guide the determination of "substantially relevant" to the growth or progression of pediatric cancer?


3. What level of evidence is necessary and would be considered substantial to predict direct benefit for institutional review boards to approve protocols for pediatric patients?


4. What types of evidence inform preliminary efficacy in molecularly targeted pediatric cancer investigations and in what phase of the clinical study would these data be collected?


5. Does the validation of the drug-target relationship have to be established in pediatric non-clinical models to be considered substantially relevant to the growth or progression of a pediatric cancer?


6. Could relevant data generated by international agencies and institutions be used in determining whether a molecular target is substantially relevant in pediatric cancer?


7. What considerations should be explored to facilitate international collaboration and coordination that address work in small patient populations?


8. Would it be helpful to have a private effort that aims to create and encourage an open-access crowd-sourcing approach for the updating and maintenance of the list of relevant molecular targets? If so, how could this crowd-sourcing effort inform the FDA's mandate to update the molecular targets list?



Peggy Eastman is a contributing writer.