Point/Counter

Should young patients with rare sarcoma subtypes be included in adult sarcoma trials?

Click here to read the Cover Story, “Deeper understanding of disease biology may expand sarcoma treatment options.”

POINT

Yes.

It is nonsense that clinical trials continue to be performed in diseases like soft tissue sarcoma with a lower age limit that excludes children when many of the individual subtypes — such as synovial sarcoma, alveolar soft part sarcoma and rhabdomyosarcoma — span the child–adult age range. It is true that tolerance of certain drugs is different between children and adults, although for cytotoxic chemotherapy, children usually are more tolerant. There were concerns that some targeted agents, such as angiogenesis inhibitors, might be particularly toxic, and might inhibit growth. However, this has not been our experience to date. Pharmaceutical companies generally have been very slow to conduct trials in children and the lack of safety data is then used as a reason to impose a lower age limit.

Ian Judson, MA, MD, FRCP
Ian Judson

There also are clear differences in prognosis across the age range, especially through adolescence. This has often been ascribed to the fact that above a certain age — such as 16 or 18 years — patients are treated by adult physicians. The view of many pediatric oncologists is that adult oncologists do not treat intensively enough. That this is the principal cause of poorer outcomes with increasing age is disputed, because evidence is accruing of important biological differences, such as increasing genetic complexity with age in synovial sarcoma, that is more likely to be responsible.

Teenagers and young adults are poorly represented in clinical trials for a variety of organizational and psychosocial reasons, and due to the lack of available trials. There are a number of initiatives to create clinical trials that will be inclusive, ensure a consistent treatment approach and study the biology across the age spectrum prospectively.

For diseases that occur with reasonable frequency in children, those children should be included in “adult” clinical trials unless there are compelling safety reasons why this cannot be done.

Ian Judson, MA, MD, FRCP, is a visiting researcher at The Institute of Cancer Research. He can be reached at ian.judson@icr.ac.uk. Disclosure: Judson reports research funding from AstraZeneca.

COUNTER

Only if pediatric considerations are taken into account.

Very young children should not be enrolled in an adult sarcoma clinical trial for the following reasons: The toxicity of the drug might be different in the younger age group; what is acceptable toxicity among children may not be acceptable toxicity among adults; and because of the need for appropriate drug formulation, especially if administered orally.

Leo Mascarenhas, MD, MS
Leo Mascarenhas

In general, very young children often are unable to swallow tablets and need palatable forms of medications. There are data in young children, particularly in those who are very young, that show pharmacokinetics may be different from that of adults and teenagers.

In general, children with cancer have better outcomes than adults. In adult trials, benchmarks for efficacy leading to drug approval are philosophically different from what one would consider in pediatrics, where the intent of primary treatment is cure. What is considered sufficient improvement based on PFS in adults may not be sufficient for us to consider as optimal for children.

There are circumstances when it is appropriate to combine adults and children in trials provided certain parameters are met. For example, at this year’s ASCO Annual Meeting, researchers presented tumor-agnostic trial data with larotrectinib (LOXO-101, Loxo Oncology), a specific tropomyosin receptor kinase (TRK) inhibitor. Researchers combined data from adult and pediatric trials of patients who had TRK mutations, and results showed clear benefit for both groups. Although the drug was being developed in adults, the drug company pursued development in children at the same time with a liquid formulation and an acceptable pediatric clinical trial design.

Often, children are not given the opportunity to be exposed to a drug that might help them because the therapy doesn’t show efficacy in an adult trial and therefore is not further developed. This is where children lose out. If there is a specific drug target of importance in pediatrics, designing a study within an adult clinical trial that takes pediatric patients into consideration would be desirable.

For certain sarcomas — such as osteosarcoma and Ewing sarcoma — if a patient is aged older than 12 or 13 years, it is not a major impediment to include those patients in an adult trial provided they meet the criteria. However, there needs to be special considerations for patients aged younger than 12 years, particularly infants, toddlers and young children.

Children are often heavily pretreated at the time they are considered eligible for phase 1 or phase 2 clinical trials and may not qualify to participate based on the eligibility criteria set in an adult trial with acceptable tolerability and toxicity monitoring. Therefore, the best way to address that barrier is to collaboratively involve pediatric oncologists and those knowledgeable of pediatric clinical trials so they can provide appropriate input during trial development.

Within the Sarcoma Alliance Research Collaboration Consortium, there is ongoing effort to include younger patients. I support this, but only if pediatric considerations are included — the formulations and pharmacokinetics in young patients are addressed appropriately and specific information is gathered for translation.

If these goals are not met and children not included, the opportunity to study them becomes even more challenging. For example, if data are already obtained from older patients, it may be difficult to run pediatric trials limited to a younger age group due to the relative smaller number of patients.

Reference:

Hyman DM, et al. Abstract LBA2501. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Leo Mascarenhas, MD, MS, is deputy director of Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles. He can be reached at lmascarenhas@chla.usc.edu. Disclosure: Mascarenhas reports research support to his institution from AstraZeneca and Eli Lilly.

Click here to read the Cover Story, “Deeper understanding of disease biology may expand sarcoma treatment options.”

POINT

Yes.

It is nonsense that clinical trials continue to be performed in diseases like soft tissue sarcoma with a lower age limit that excludes children when many of the individual subtypes — such as synovial sarcoma, alveolar soft part sarcoma and rhabdomyosarcoma — span the child–adult age range. It is true that tolerance of certain drugs is different between children and adults, although for cytotoxic chemotherapy, children usually are more tolerant. There were concerns that some targeted agents, such as angiogenesis inhibitors, might be particularly toxic, and might inhibit growth. However, this has not been our experience to date. Pharmaceutical companies generally have been very slow to conduct trials in children and the lack of safety data is then used as a reason to impose a lower age limit.

Ian Judson, MA, MD, FRCP
Ian Judson

There also are clear differences in prognosis across the age range, especially through adolescence. This has often been ascribed to the fact that above a certain age — such as 16 or 18 years — patients are treated by adult physicians. The view of many pediatric oncologists is that adult oncologists do not treat intensively enough. That this is the principal cause of poorer outcomes with increasing age is disputed, because evidence is accruing of important biological differences, such as increasing genetic complexity with age in synovial sarcoma, that is more likely to be responsible.

Teenagers and young adults are poorly represented in clinical trials for a variety of organizational and psychosocial reasons, and due to the lack of available trials. There are a number of initiatives to create clinical trials that will be inclusive, ensure a consistent treatment approach and study the biology across the age spectrum prospectively.

For diseases that occur with reasonable frequency in children, those children should be included in “adult” clinical trials unless there are compelling safety reasons why this cannot be done.

Ian Judson, MA, MD, FRCP, is a visiting researcher at The Institute of Cancer Research. He can be reached at ian.judson@icr.ac.uk. Disclosure: Judson reports research funding from AstraZeneca.

PAGE BREAK

COUNTER

Only if pediatric considerations are taken into account.

Very young children should not be enrolled in an adult sarcoma clinical trial for the following reasons: The toxicity of the drug might be different in the younger age group; what is acceptable toxicity among children may not be acceptable toxicity among adults; and because of the need for appropriate drug formulation, especially if administered orally.

Leo Mascarenhas, MD, MS
Leo Mascarenhas

In general, very young children often are unable to swallow tablets and need palatable forms of medications. There are data in young children, particularly in those who are very young, that show pharmacokinetics may be different from that of adults and teenagers.

In general, children with cancer have better outcomes than adults. In adult trials, benchmarks for efficacy leading to drug approval are philosophically different from what one would consider in pediatrics, where the intent of primary treatment is cure. What is considered sufficient improvement based on PFS in adults may not be sufficient for us to consider as optimal for children.

There are circumstances when it is appropriate to combine adults and children in trials provided certain parameters are met. For example, at this year’s ASCO Annual Meeting, researchers presented tumor-agnostic trial data with larotrectinib (LOXO-101, Loxo Oncology), a specific tropomyosin receptor kinase (TRK) inhibitor. Researchers combined data from adult and pediatric trials of patients who had TRK mutations, and results showed clear benefit for both groups. Although the drug was being developed in adults, the drug company pursued development in children at the same time with a liquid formulation and an acceptable pediatric clinical trial design.

Often, children are not given the opportunity to be exposed to a drug that might help them because the therapy doesn’t show efficacy in an adult trial and therefore is not further developed. This is where children lose out. If there is a specific drug target of importance in pediatrics, designing a study within an adult clinical trial that takes pediatric patients into consideration would be desirable.

For certain sarcomas — such as osteosarcoma and Ewing sarcoma — if a patient is aged older than 12 or 13 years, it is not a major impediment to include those patients in an adult trial provided they meet the criteria. However, there needs to be special considerations for patients aged younger than 12 years, particularly infants, toddlers and young children.

Children are often heavily pretreated at the time they are considered eligible for phase 1 or phase 2 clinical trials and may not qualify to participate based on the eligibility criteria set in an adult trial with acceptable tolerability and toxicity monitoring. Therefore, the best way to address that barrier is to collaboratively involve pediatric oncologists and those knowledgeable of pediatric clinical trials so they can provide appropriate input during trial development.

Within the Sarcoma Alliance Research Collaboration Consortium, there is ongoing effort to include younger patients. I support this, but only if pediatric considerations are included — the formulations and pharmacokinetics in young patients are addressed appropriately and specific information is gathered for translation.

If these goals are not met and children not included, the opportunity to study them becomes even more challenging. For example, if data are already obtained from older patients, it may be difficult to run pediatric trials limited to a younger age group due to the relative smaller number of patients.

Reference:

Hyman DM, et al. Abstract LBA2501. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Leo Mascarenhas, MD, MS, is deputy director of Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles. He can be reached at lmascarenhas@chla.usc.edu. Disclosure: Mascarenhas reports research support to his institution from AstraZeneca and Eli Lilly.