Point/Counter

Should criteria for adult oncology trials be relaxed so those aged younger than 18 years can participate?

Click here to read the Cover Story, “Strict cancer trial eligibility criteria ensure patient safety, but ‘pendulum has swung too far.’”

POINT

Yes, the age criteria should be relaxed.

Older teenagers are physiologically more similar to adults than they are to toddlers in some regards, and they typically have pharmacokinetics and metabolism similar to adults.

Lia Gore, MD
Lia Gore

In general, drug exposure and metabolism are similar after puberty throughout adulthood and, as such, the age at which patients reach physiological maturity might be a more appropriate benchmark than a nominal age cutoff.

Patients with diseases that occur across pediatric and adult age groups — such as some lymphomas, osteosarcoma, Ewing sarcoma and some leukemias — could be included on adult clinical trials when there is good biological evidence that the therapy targets the driver oncogenic pathway(s) that are similar or identical. Examples include an anti-CD30 antibody used to treat Hodgkin lymphoma or anaplastic large cell lymphoma, or a BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia. These targets and mechanisms of action are identical whether a patient is aged 13 years or 55 years. If safety and efficacy data are available, there is little reason to limit the access these patients have to potentially beneficial therapies strictly on the basis of age.

There are some treatments that could be made available to patients aged younger than 18 years — particularly if there are initial toxicity data and strong scientific rationale for likelihood of benefit based on molecular pathways or biologic drivers — even if the primary disease in children is different from that in adults. An example would be ALK-mutated non-small cell lung cancer among adults and ALK-mutant neuroblastoma among children.

Younger patients could be included on select adult trials. If there are concerns about enrolling younger patients, separate pediatric cohorts that open one dose level below the safely defined dose for the adult cohort could be employed.

After discussion, both Peter C. Adamson, MD, and I agree that now that we have such substantial advances in many therapies that provide rational choices for target inhibition, it is time that we modernize the eligibility criteria and expectations to ensure that we offer the right treatments to the patients who can benefit from them the most within a context of safety and appropriateness. This will not only offer our patients the best opportunities, but will make drug development more efficient, thus putting the effort and investments in the right places.

Lia Gore, MD, is professor of pediatrics, medical oncology and hematology at University of Colorado Anschutz Medical Campus, as well as Ergen family endowed chair in pediatric oncology at Children’s Hospital Colorado. She can be reached at lia.gore@ucdenver.edu. Disclosure: Gore reports no relevant financial disclosures.

COUNTER

There are potential benefits to relaxing the age criteria, but a pediatric drug development plan is still necessary.

Lowering the eligibility age threshold for certain medical oncology cancer clinical trials makes a great deal of sense — especially for early-phase, investigational phase cancer drug studies. There are adolescent patients with relapsed or refractory cancers with no known effective treatment options who are interested in, and potentially could benefit from, participating in such studies. Access to clinical trials is critically important for such patients because pediatric cancer studies too often lag far behind adult clinical trials.

Peter C. Adamson, MD
Peter C. Adamson

It is important to note that, although such a change is logical and welcome, it will not obviate the need for — nor should it delay — a pediatric drug development plan. The number of adolescents who would participate in any one study is likely to be very small, and informative data from such participation will be limited. Although it is conceivable that a signal might emerge from those adolescents who are able to participate, it will not provide the requisite data needed for drugs that have potential benefit for one or more childhood cancers.

Logistically, the changes needed to clinical trials are manageable. There still would be a potential need to scale the dose of the drug to a body metric, such as body surface area or weight, especially for younger adolescents. Given current regulations that afford additional protection to children participating in research, the doses to be studied would have to be reasonably likely to produce a biologic effect, so the first doses in dose escalation trials may not be amenable to pediatric participation. Importantly, representatives from adult cancer centers may need to collaborate directly with pediatric oncologists within their institution to help ensure appropriate management of participating patients.

Peter C. Adamson, MD, is chair of Children’s Oncology Group, as well as Alan R. Cohen endowed chair in pediatrics at The Children’s Hospital of Philadelphia. He can be reached at adamson@email.chop.edu. Disclosure: Adamson reports no relevant financial disclosures.

Click here to read the Cover Story, “Strict cancer trial eligibility criteria ensure patient safety, but ‘pendulum has swung too far.’”

POINT

Yes, the age criteria should be relaxed.

Older teenagers are physiologically more similar to adults than they are to toddlers in some regards, and they typically have pharmacokinetics and metabolism similar to adults.

Lia Gore, MD
Lia Gore

In general, drug exposure and metabolism are similar after puberty throughout adulthood and, as such, the age at which patients reach physiological maturity might be a more appropriate benchmark than a nominal age cutoff.

Patients with diseases that occur across pediatric and adult age groups — such as some lymphomas, osteosarcoma, Ewing sarcoma and some leukemias — could be included on adult clinical trials when there is good biological evidence that the therapy targets the driver oncogenic pathway(s) that are similar or identical. Examples include an anti-CD30 antibody used to treat Hodgkin lymphoma or anaplastic large cell lymphoma, or a BCR-ABL tyrosine kinase inhibitor for chronic myeloid leukemia. These targets and mechanisms of action are identical whether a patient is aged 13 years or 55 years. If safety and efficacy data are available, there is little reason to limit the access these patients have to potentially beneficial therapies strictly on the basis of age.

There are some treatments that could be made available to patients aged younger than 18 years — particularly if there are initial toxicity data and strong scientific rationale for likelihood of benefit based on molecular pathways or biologic drivers — even if the primary disease in children is different from that in adults. An example would be ALK-mutated non-small cell lung cancer among adults and ALK-mutant neuroblastoma among children.

Younger patients could be included on select adult trials. If there are concerns about enrolling younger patients, separate pediatric cohorts that open one dose level below the safely defined dose for the adult cohort could be employed.

After discussion, both Peter C. Adamson, MD, and I agree that now that we have such substantial advances in many therapies that provide rational choices for target inhibition, it is time that we modernize the eligibility criteria and expectations to ensure that we offer the right treatments to the patients who can benefit from them the most within a context of safety and appropriateness. This will not only offer our patients the best opportunities, but will make drug development more efficient, thus putting the effort and investments in the right places.

Lia Gore, MD, is professor of pediatrics, medical oncology and hematology at University of Colorado Anschutz Medical Campus, as well as Ergen family endowed chair in pediatric oncology at Children’s Hospital Colorado. She can be reached at lia.gore@ucdenver.edu. Disclosure: Gore reports no relevant financial disclosures.

PAGE BREAK

COUNTER

There are potential benefits to relaxing the age criteria, but a pediatric drug development plan is still necessary.

Lowering the eligibility age threshold for certain medical oncology cancer clinical trials makes a great deal of sense — especially for early-phase, investigational phase cancer drug studies. There are adolescent patients with relapsed or refractory cancers with no known effective treatment options who are interested in, and potentially could benefit from, participating in such studies. Access to clinical trials is critically important for such patients because pediatric cancer studies too often lag far behind adult clinical trials.

Peter C. Adamson, MD
Peter C. Adamson

It is important to note that, although such a change is logical and welcome, it will not obviate the need for — nor should it delay — a pediatric drug development plan. The number of adolescents who would participate in any one study is likely to be very small, and informative data from such participation will be limited. Although it is conceivable that a signal might emerge from those adolescents who are able to participate, it will not provide the requisite data needed for drugs that have potential benefit for one or more childhood cancers.

Logistically, the changes needed to clinical trials are manageable. There still would be a potential need to scale the dose of the drug to a body metric, such as body surface area or weight, especially for younger adolescents. Given current regulations that afford additional protection to children participating in research, the doses to be studied would have to be reasonably likely to produce a biologic effect, so the first doses in dose escalation trials may not be amenable to pediatric participation. Importantly, representatives from adult cancer centers may need to collaborate directly with pediatric oncologists within their institution to help ensure appropriate management of participating patients.

Peter C. Adamson, MD, is chair of Children’s Oncology Group, as well as Alan R. Cohen endowed chair in pediatrics at The Children’s Hospital of Philadelphia. He can be reached at adamson@email.chop.edu. Disclosure: Adamson reports no relevant financial disclosures.