FDA: More adolescents with cancer should be included in adult trials

Enrollment of adolescents in oncology trials remains significantly lower than that of children.

Perspective from Anjali S. Advani, MD

Consequently, the FDA has urged the research community to enroll more adolescents with cancer in clinical trials designed to evaluate investigational oncology treatments in adults.

Meredith Chuk

“The inclusion of adolescents in adult oncology trials will require the cooperation of investigators, cooperative groups, industry, institutional review boards and regulatory agencies to overcome real and perceived barriers,” Meredith Chuk, MD, pediatric oncologist and medical officer in the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, and colleagues wrote in Clinical Cancer Research.

The low rate of adolescent involvement in clinical trials is not new.

In 1983, NCI created the Community Clinical Oncology Program (CCOP) — now known as the National Community Oncology Research Program — to increase access for all patients to clinical trials in the community setting. Despite this effort, data suggest that only about 10% of adolescents with cancer are enrolled on clinical trials.

A study published in 2016 in Journal of Oncology Practice showed that CCOP sites enrolled more patients overall in cancer-control studies than non–CCOP sites (3.5% vs. 1.8%; P < .001), the proportion of adolescents and young adults enrolled was lower at CCOP sites (24.1% vs. 28.2%; P < .001). In addition, enrollment of adolescents and young adults across CCOP sites decreased from 26.7% between 2004 and 2008 to 21.7% between 2009 and 2013 (P < .001).

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HemOnc Today spoke with Chuk about how the FDA recommendation came about, as well as what members of the clinical community need to know about the importance of enrolling adolescents with cancer on clinical trials.

Question: How did this recommendation come about?

Answer: Adolescents with cancer traditionally have had much lower enrollment in clinical trials than younger pediatric patients. Pediatric drug development generally is isolated from drug development in adults and often follows it by many years. The recommendation of enrolling more adolescents on relevant adult clinical trials in oncology will allow these patients earlier and increased access to investigational and approved drugs.

Q: Why is this recommendation needed?

A: Clinical trial participation has contributed to the 50% decline in overall childhood cancer mortality since 1975, but adolescents and young adults have not seen the same level of improvements in survival. We are seeing continued disparities in survival improvements for some cancers, which tend to be the cancers that are similar to those seen in adults. Enrolling adolescents early in drug development programs can allow for the inclusion of adolescents in the indication at the time of initial FDA approval. It also can expedite access to new drugs for these patients.

Q: Why is adolescent enrollment into clinical trials lagging behind where it should be?

A: The reason for lower enrollment of adolescents onto clinical trials in oncology is multifactorial. Lack of availability of trials specifically for this age group and their exclusion from adult cancer trials are important reasons. Other reasons include lack of access to available trials depending on the location of care of the patient, and nonreferral by community oncologists to centers where trials exist.

Q: Why are adolescents more similar to adults than younger pediatric patients?

A: Many tumors that occur in adolescents — such as some soft tissue and bone sarcomas, central nervous system tumors, leukemias, lymphomas and melanoma — differ from tumors in younger pediatric patients and are similar in biology to the same tumors seen in adults. In addition, drug dosing has been shown to be similar in adolescents and adults. Drug dosing is an important consideration for safety and efficacy, and it depends largely on elimination clearance of the drug. Studies have shown that the clearance of many drugs are similar in adolescents and adults once the effect of body size is considered. In an FDA review described in our paper, the authors reported that — for the drugs reviewed — clearance in adolescents was similar to adults, and drug dosing was identical in 95% of the cases. This is a pharmacokinetic justification for including adolescents aged 12 to 17 years on appropriately selected adult trials. For drugs that use body-weight dosing, the same dose can be used in adolescents and adults. For drugs that use fixed dosing, it may be necessary to establish a minimum body weight threshold in adolescents, depending on how much body weight affects the pharmacokinetics of the drug under evaluation.

Q: What do clinicians need to know about the importance of enrolling adolescents on trials?

A: Enrolling adolescents on adult oncology trials can provide faster access to effective therapies for life-threatening diseases. Clinical trials also offer regulatory and safety oversight, and they generate important data to inform the safe and effective use of new therapies in the adolescent population. – by Jennifer Southall

References:

Chuk MK, et al. Clin Cancer Res. 2016;doi:10.1158/1078-0432.CCR-16-1367.

Roth ME, et al. J Oncol Pract. 2016;doi:10.1200/JOP.2015.009084.

For more information:

Meredith Chuk, MD, can be reached at Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD 20993; email: meredith.chuk@fda.hhs.gov.

Disclosure: Chuk reports no relevant financial disclosures.

Perspective

Anjali S. Advani, MD

Over the last decade, several studies have consistently demonstrated a benefit to a pediatric-inspired approach in the treatment of adolescents and young adults with acute lymphoblastic leukemia. The FDA has suggested that adolescents should be enrolled in disease/target-appropriate adult oncology clinical trials of investigational agents. Although the two statements may seem disparate, they are not. Even within ALL, the development of novel antibody-based treatment strategies in the relapsed/refractory setting have developed significantly more rapidly in the adult setting, and many of these initial trials have excluded patients aged younger than 18 years, despite the fact that pharmacology, dosing and safety of most agents is very similar in the adolescent and adult population.
Because the Philadelphia (Ph) chromosome occurs much less frequently in childhood ALL, the initial trials of tyrosine kinase inhibitors in combination with chemotherapy for Ph+ALL in adolescents also lagged significantly behind those in adults. Even now, most of the trials with the second and third TKIs exclude patients aged younger than 18 years. However, the initial trials with imatinib plus intensive chemotherapy for Ph+ALL in children and adolescents clearly improved outcomes for these patients, despite the fact that this may be a small subgroup of patients.
Finally, acute myeloid leukemia is more prevalent in adults than children and more targeted therapies have been developed within the adult realm. One example is the phase 3 RATIFY trial. Researchers of this trial randomly assigned adults with newly diagnosed AML (aged 18-59 years) with FLT3 mutations to chemotherapy alone or with the FLT3 inhibitor midostaurin (PKC412, Novartis). The addition of midostaurin improved OS in patients with FLT3 mutations, and midostaurin likely will be FDA approved for this indication. However, even within the context of this trial, adolescents were not treated, and so this group is unlikely to be included in the label of the drug.
Although pediatric-inspired approaches and trials may be beneficial in the adolescent and young adult population, ensuring access to novel agents in the setting of relapsed/refractory disease and in specific biologic subsets with targeted therapy is critical to increasing clinical trial accrual and improving clinical outcomes for adolescents with cancer. Although there may be logistical and regulatory hurdles to inclusion of these patients in trials, these obstacles are surmountable and will require collaboration and support of pediatric and adult hematologist/oncologists.

References:

Schultz KR, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2008.21.2514.
Stone RM, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Anjali S. Advani, MD

Cleveland Clinic

Disclosures: Advani reports research support from Amgen, and a consultant role with and research support from Pfizer.