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Trial assesses targeted therapies for solid tumors in children
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A nationwide trial will assess targeted therapies for children and adolescents.
The NCI-Children’s Oncology Group (COG) Pediatric MATCH trial will enroll patients who have solid tumors with genetic mutations, and who progressed on prior therapies.
“This trial would not have been possible without the enthusiastic support of the partnering pharmaceutical companies, as evidenced by their willingness to provide targeted agents for this trial,” Nita Seibel, MD, head of pediatric solid tumor therapeutics in the Clinical Investigations Branch of the Cancer Therapy and Evaluation Program at NCI, said in a press release. “Some of the agents included have not previously been tested in children, so this trial will provide broader access to targeted agents for children and adolescents.”
HemOnc Today spoke with Seibel about how the trial came about, how it will be conducted and the insights it may offer for the pediatric oncology community.
Question: What prompted this research?
Answer: Within the past decade, the technology to sequence tumors has evolved and the costs have decreased. We are able to develop more sophisticated panels and cover a wider array of genes. We now have more information about tumors and the type of genetic aberrations that are present in the tumors, in parallel to agents that target some of these abnormalities identified in tumors. As we have learned more about the biology of tumors, it is natural that we would want to extend this — particularly in pediatric oncology, to see if we can target those genetic abnormalities with a specific agent and assess the type of impact this will have on pediatric tumors. That was the stimulus for doing this trial, and it is part of the precision medicine movement that has been going on in adults with cancer and in, a limited manner, in pediatrics. It is only natural that we would examine this on a much wider scale in the pediatric population.
Q: How will the study be conducted?
A: Eligible participants include children aged 1 to 21 years with a solid tumor that has failed on standard therapy, meaning the tumor did not respond to therapy or it recurred. Patients with recurrent tumors will be eligible if they had a biopsy since the time the tumor recurred or progressed. One exception is patients with brain-stem gliomas. The location of these tumors can make biopsy risky so, for this group, we will accept a biopsy done at the time of diagnosis. The treating pediatric oncologist will send tumor tissue to the COG Biopathology Center at Nationwide Children’s Hospital. DNA and RNA will be extracted and sent to one of two laboratories — either the Molecular Characterization Lab at Frederick National Laboratory for Cancer Research or The University of Texas MD Anderson Cancer Center. The nucleic acids will be analyzed by the NCI-MATCH next-generation sequencing assay, which can identify the presence or absence of more than 3,000 mutations of interest in more than 160 genes. Immunohistochemistry also will be performed to further identify the molecular characteristics of the tumor.
The treating pediatric oncologist will receive a report describing any genetic aberrations identified and whether they match one of the therapeutic arms in the trial. Patients and their families will decide if they want to participate in that specific treatment arm of the study. Patients can stay on treatment as long as their tumors are responding.
Patients who progress will be eligible to move to another arm of the trial if the treatment targets another genetic abnormality identified in their tumor. If a patient who progresses does not harbor any other genetic abnormalities that correspond with treatment arms, he or she will come off the treatment portion of the study.
Q: How will this study differ from NCI-MATCH, a similar trial for adults that began enrolling patients in 2015?
A: In addition to submitting tumor tissue, a tube of peripheral blood will be sent to the biopathology center. DNA will be extracted, and a clinical geneticist will review germline DNA analysis to determine whether the genetic abnormalities in the tumor were inherited. The treating oncologist will decide whether the family should have further genetic testing or counseling to identify potential risks that may affect other children in the family.
Biopsy timing is different. For NCI-MATCH, the biopsy was done at the time of study enrollment. For Pediatric MATCH, we are willing to accept a biopsy obtained several weeks or months before, as long as it is from the time of progression or recurrence of the tumor.
The number of arms in each trial also is different. There are more than 30 treatment arms in the trial for adults. There are seven treatment arms in the pediatric trial, and we will add at least two more in the next several months. Tumors that occur in adults have many more mutations and genetic aberrations than tumors that occur in children and adolescents. Because there are fewer mutations, we do not have as many targeted agents available for pediatric cancers.
Q: What is the trial timeline?
A: We project that between 200 and 300 patients will be enrolled each year on Pediatric MATCH. We expect to screen around 1,000 patients. It is hard to say when we can expect results because it is difficult to estimate how quickly each treatment arm will accrue patients who have tumors with specific genetic abnormalities. We anticipate that approximately 10% of the children and adolescent patients screened will match to one of the therapeutic arms.
Q: What is your hope for the trial?
A: Our hope is that we will match patients’ tumors to treatment, and that the tumors will respond to that treatment. This study is meant to be a screening tool, to see if there is a hint of activity. We hypothesize that, if we target a specific genetic abnormality that is present in the tumor with an agent that is specific for that abnormality, the tumor will respond. Twenty patients will be enrolled into each treatment arm and, if we see responses in three or more of the patients on that treatment arm, this will be considered an interesting result. We then will do additional studies with that agent. We have built into the protocol that, if three of 20 patients achieve response, we will enroll additional patients on that particular treatment arm to get a better idea of the drug’s activity. This is the best-case scenario.
Q: Is there anything else that you would like to mention?
A: Pediatric MATCH is a unique trial. There are ongoing studies in the United States and internationally in which tumors are sequenced, but this study is unique because treatment arms are incorporated in the trial and the trial is being conducted with the COG. Therefore, a large number of institutions — more than 200 in the United States — will have access to the trial for their patients. Another remarkable aspect of the trial is the huge amount of team effort that has taken place between COG, NCI, the FDA and many pharmaceutical companies to develop this trial. It was exciting and very gratifying to see the enthusiasm from the pharmaceutical companies. They really want to play a role in helping to find cures for children and adolescents with cancer. – by Jennifer Southall
For more information:
Nita Seibel, MD, can be reached at National Cancer Institute, 9609 Medical Center Drive, RM 5W340, Bethesda, MD 20892; email: seibelnl@mail.nih.gov.
Disclosure: Seibel reports no relevant financial disclosures.