Differences in Absolute Neutrophil Count Eligibility Criteria of Pediatric Phase I and Phase I/II Oncology Clinical Trials According to Sponsorship
Authors: Kelly Rebecca , Ruiz Jenny , Aplenc Richard , Laetsch Theodore W. , Seif Alix E. 
Published: December 2023

Introduction: Racial clinical trial enrollment disparities in oncology are well documented ( Pediatr Blood Cancer. 2020 10.1002/pbc.28296). Barriers to enrollment are multifactorial and include structural and clinical barriers like restrictive eligibility criteria ( Am Soc Clin Oncol Educ Book. 2016 10.1200/EDBK_156686). Many phase I/II oncology clinical trials have laboratory criteria such as a minimum threshold for absolute neutrophil count (ANC). The Common Terminology Criteria for Adverse Events (CTCAE) defines an ANC of less than 1500 cells/µL as the upper limit of a grade 2 toxicity ( J Clin Oncol. 2010 10.1200/JCO.2009.24.3881), and this has become the minimum eligibility threshold in many oncology trials ( J Clin Oncol. 2017 10.1200/JCO.2017.73.4186). Using a minimum ANC of 1500 cells/µL may contribute to further racial enrollment disparities due to the Duffy null phenotype, which has a prevalence of ~65% in Black/African American individuals ( PLoS Genet. 2011 10.1371/journal.pgen.1002108) and results in a lower number of circulating neutrophils compared to people without the Duffy null phenotype ( Blood. 2021 10.1182/blood.2020008600). Up to 23% of pediatric patients with the Duffy null phenotype have ANCs &lt;1500 cells/µL ( Blood Adv. 2023 10.1182/bloodadvances.2022007680). A recent adult multiple myeloma study found that the most common reason for ineligibility among Black patients was failure to meet hematologic laboratory criteria ( Blood. 2023 10.1182/blood.2022018657). Less is known about eligibility criteria as a barrier to enrollment in the pediatric cancer population. We hypothesized industry-sponsored trials would have more restrictive eligibility criteria than non-industry-sponsored trials. To explore this further we describe ANC eligibility criteria of pediatric oncology phase I/II clinical trials according to sponsorship.

Methods: We analyzed ANC eligibility criteria of interventional phase I and phase I/II oncology trials opened in the United States from January 2010 to May 2023 using the ClinicalTrials.gov registry. Trials that included pediatric participants only (up to age 18), pediatric and adolescent young adult participants (up to age 39), and adult studies that allowed pediatric participants were included. We excluded trials for non-malignant conditions and trials that did not report ANC eligibility criteria. ANC eligibility criteria were categorized as ≥1500 cells/µL and &lt;1500 cells/µL. Trials were compared according to primary sponsorship (industry vs non-industry). Secondary objective was to describe language requirements explicitly mentioned for these trials. Distribution of trial characteristics were compared using Fisher's exact or Chi-squared tests. Logistic regression was used to evaluate potential changes in ANC criteria over time (in years), using ANC&lt;1500 cells/µL as the reference group.

Results: We identified 861 interventional trials that met our initial inclusion criteria. After review of the trials, 36 were excluded for enrolling participants with non-malignant diagnoses. Of the remaining 825 studies, 438 (53%) had ANC eligibility criteria reported. 89 (20%) studies were industry-sponsored (Table 1). Trial phase, age eligibility, diagnosis, and results reported differed statistically significantly by sponsor type. 76 (17%) studies required ANC ≥1500 cells/µL for enrollment. For industry sponsored trials, 26 (29%) required ANC ≥1500, while 50 (14%) non-industry sponsored trials required ANC ≥1500, with a risk ratio of 2.04 (95% CI 1.35-3.08, p=0.002) (Figure 1). Almost all studies (96%) did not explicitly state language requirements, and this did not vary by sponsor type. There was no significant change in odds of a trial requiring ANC ≥1500 cells/µL over time (odds ratio 1.05, 95% CI 0.98-1.12, p=0.138).

Conclusion: A minority of trials (17%) required an ANC ≥1500 cells/µL for enrollment on a phase I or phase I/II interventional clinical oncology trial; however, industry-sponsored trials were twice as likely than non-industry trials to require this higher ANC threshold. Further studies are needed to investigate laboratory criteria as a possible reason for racial enrollment disparities in pediatric cancer trials.