NEW YORK (GenomeWeb) – Plans for a precision medicine clinical trial for pediatric cancer called NCI Pediatric MATCH are starting to take shape, with enrollment expected to start by the end of this year, GenomeWeb has learned.
The study, which has been in the works since last year, will be the pediatric counterpart to the ongoing NCI-MATCH trial, which launched last June and only accepts cancer patients 18 years and older.
Pediatric MATCH, which stands for Molecular Analysis for Therapy Choice, "provides a tremendous opportunity to test molecularly targeted therapies in children with advanced cancers who have few other treatment options" and "will also produce an invaluable resource for studying the genetic basis of pediatric cancers," according to the National Cancer Institute.
NCI will run the study in partnership with the Children's Oncology Group (COG), an NCI-supported clinical trials group that includes more than 200 children's hospitals, universities, and cancer centers in the US, Canada, Australia, New Zealand, and Europe.
"We are hoping to have a protocol submitted for review within the next month," Will Parsons, an associate professor at Baylor College of Medicine and Texas Children's Cancer Center, told GenomeWeb, and the goal is to open the study by the end of the year. Parsons is the study chair for the COG — the other study leader is Nita Seibel of the NCI's Cancer Therapy Evaluation Program.
Pediatric MATCH will enroll patients with solid tumors who have progressed following at least one line of standard systemic therapy, or patients for whom no standard treatment that prolongs survival exists. The organizers currently project enrolling on the order of 300 patients per year for screening — fewer than NCI-MATCH, which plans to enroll 3,000 patients for screening and signed up almost 800 within the first few months — though "until we open, we won't know," Parsons said.
Similar to NCI-MATCH, a biopsy of the patient's tumor will be screened for genetic alterations, using a targeted gene sequencing test that is based on Thermo Fisher Scientific's Oncomine panel and runs on the Ion PGM sequencer. According to Parsons, the panel is being modified by a committee that has reviewed pediatric cancer genomic data to include additional alterations that are of particular relevance to childhood cancers.
Samples will initially be sequenced at two sites — the NCI Frederick National Laboratory for Cancer Research's Molecular Characterization Laboratory and one other yet-to-be-determined lab — though additional clinical sequencing labs may be added later.
Based on genomic abnormalities found in genes on the panel, patients will be matched to molecularly targeted agents, if possible. "We are testing the hypothesis that specific genetic alterations that we can identify will predict drug sensitivity," Parsons said. And while it is possible that other types of markers — for example, gene expression profiles — might also be useful in predicting drug sensitivity, this study will focus on genetic mutations.
The goal is to open the study with "at least a handful" of drugs, or study arms. More arms may be added over time, Parsons said, as additional information about new drugs in development becomes available. However, the study will not include targeted drugs that are already used as standard of care, for example crizotinib, a first-generation ALK inhibitor.
A target and agent prioritization (TAP) committee has been reviewing clinical data on molecularly targeted drugs and their potential relevance to pediatrics and has come up with a list of priority agents, he said, and the study organizers are currently talking to pharmaceutical companies about getting access to their drugs for the trial.
While similar in many aspects to NCI-MATCH, which is currently on hold for an interim analysis, Pediatric MATCH will differ from the adult study in some areas.
One important difference is that the study plans to sequence not only a patient's tumor but also, in parallel, a blood sample, and to report both tumor and germline alterations. A number of studies over the last year or so — including one that is scheduled to be published by Baylor researchers later this week — have found that on the order of 8 to 10 percent of pediatric cancer patients harbor germline mutations in cancer susceptibility genes, Parsons said. "Given that frequency, we think that it's important for this pediatric study that we also sequence blood samples from the patients."
Any germline mutations in cancer predisposition genes would be of relevance not only for the patient but also for family members, who could undergo enhanced cancer screening, and interpreting and reporting back germline results will likely involve geneticists or genetic counselors, he said.
The current NCI-MATCH study sequences tumor tissue only but does note in its test report whenever a mutation in a cancer susceptibility gene is found, recommending that the patient considers further evaluation to determine whether it is a germline mutation. But in pediatric cancer, the frequency of germline mutations may be higher than in adults, and members of the Children's Oncology Group are used to conveying this type of information to families, Parsons said, warranting the extra step of sequencing blood samples.
Another difference to the adult study is that some molecular targets and drugs used in NCI-MATCH are less relevant in pediatric cancers and will therefore not be included. For example, lung cancer and other adult tumors with EGFR alterations can be treated with EGFR inhibitors, but such EGFR mutations are rare in children.
Overall, one of the big concerns is that Pediatric MATCH will be able to match a large enough number of patients to make it useful. "In children, we have far fewer numbers of patients with each disease," Parsons said, so the organizers need to pick drugs that rely on mutations that can be found in a large enough number of children.
In addition, for some drugs, no safety and toxicity information is available for pediatric patients because they have not been tested in children yet. "If there is an exciting drug … we will consider using it in our study, even though we don't yet have the phase I pediatric data," he said, but for those drugs, the study will need to incorporate some initial assessment of safety and dosing.
As for all clinical studies, a number of steps are still required before Pediatric MATCH can take off. This includes the formulation of the screening protocol and the protocols for the specific arms, agreements with pharmaceutical companies about the use of their drugs, a risk assessment by the US Food and Drug Administration, and a review by the central Internal Review Board.
The risk assessment will include tumor biopsies in children, which have not been performed routinely for relapse tumors in the past. "But that context has rapidly changed over the last few years with the explosion of knowledge of genomic information, and the idea that there might be something one could learn about the recurrent tumor that might dictate treatment approaches," Parsons said, adding that biopsy risk is not known to differ significantly between children and adults.