Cancer Trial Eligibility and Therapy Modifications for Individuals With Duffy Null–Associated Neutrophil Count

Key Points Question Do cancer clinical trials and anticancer regimens restrict participation of individuals with Duffy null–associated absolute neutrophil counts (DANCs) by setting exclusions and dose modifications within their neutrophil reference range? Findings In this cross-sectional analysis of 289 phase 3 trials and 71 curative-intent anticancer regimens for the 5 most prevalent US and UK cancers, 77% of trials and 54% of regimens excluded or modified doses for patients with neutrophil counts within the DANC reference range. Meaning These findings suggest that eligibility criteria and dose modifications structurally inhibit individuals with DANC from participating in trials and obtaining appropriate anticancer therapy.

Database selection: clinicaltrials.govwas selected as the database of choice because US and UK regulations mandate registration and publication of US clinical trial records on this site, it captures a large number of global clinical trials, and it supplies adequate data fields for selecting trials of interest.As UK regulations allow trials to be alternatively registered on ISRCTN, we assessed the coverage gap of using clinicaltrials.govalone by performing a search of cancer clinical trials registered on ISRCTN and reviewing a random selection of 20 trial records that fit the search criteria below to assess for cross-registration on clinicaltrials.gov.As 100% of this selection was cross-registered, the search and data extraction were limited to clinicaltrials.gov.
Search: The following searches were performed using the categories and options available on clinicaltrials.gov.If a category or option is not mentioned, it was not included in the search.Separate searches were performed for each condition/disease term listed.Of note, the searches were not restricted to trials based in the United States or United Kingdom, but a sensitivity analysis of those trials was performed.All searches were performed on 3 November 2023.
-Condition/Disease: ( Of note, Food and Drug Administration (FDA) label search and analysis was performed separately as the regimen-based modifications were thought to account for emergent toxicities from combination therapy that may not be addressed in individual agent labels.
Search: SACT Regimens: NCCN Clinical Practice Guidelines in Oncology Evidence Blocks for breast cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, and cutaneous melanoma were obtained on 11 February 2024.Two study team members independently reviewed the guidelines and identified and verbatim catalogued "Preferred" SACT regimens used during curative treatment and the citations supporting the use of the regimen.After screening, the clinical trial manuscripts referenced were identified through PubMed and available study protocols were obtained.UpToDate was searched between 20 February and 6 March 2024 to identify the regimen's treatment protocol (e.g., "Treatment Protocols for Non-small Cell Lung Cancer," available at uptodate.com/contents/treatmentprotocols-for-non-small-cell-lung-cancer).
FDA Labels: After regimen screening was completed, each SACT agent was catalogued.Drugs@FDA (www.accessdata.fda.gov/scripts/cder/daf/index.cfm) was queried between 25 February and 3 March 2024 with the agent's name, and the most recent New Drug Application label was reviewed.If no New Drug Application label was available, the most recent Abbreviated New Drug Application label was reviewed.

Screening:
SACT Regimens: Each reviewer screened the regimens that were identified and removed regimens for the following reasons: duplicate regimens, regimens that could not be confirmed as Preferred, and regimens that were not independent treatments (i.e., maintenance therapy only given after another SACT regimen).Screening results are shown in eFigure 2.
FDA Labels: There was no screening of FDA labels beyond ensuring the correct agent and New Drug Application label was being reviewed.

Data Extraction:
SACT Regimens: Protocols were the preferred source of recommended dose modifications.When a protocol was available, each reviewer reviewed the latest version of the protocol and dose modifications were catalogued verbatim.When a protocol was not available, the manuscript was reviewed, and dose modifications catalogued if available.When neither had dose modification information, UpToDate was reviewed, and the dose modification listed was catalogued.Regimens were independently categorized into the mutually exclusive categories of explicitly modifying, implicitly modifying, or not modifying, using analogous criteria to the CCT Eligibility analysis.Each citation for a given regimen was reviewed, and if there were discrepancies between dose modification categories between trials referenced, the less restrictive categorization was retained.Discrepancies were resolved by consensus, with a third reviewer adjudicating if needed.
FDA Labels: Each SACT agent used in a regimen was reviewed and dose modification information was catalogued verbatim and categorized as outlined above.Information from each agent was then assessed as a regimen, and the most restrictive categorization was retained.
Discrepancies were resolved by consensus, with a third reviewer adjudicating if needed.
each performed as separate search) .Hormonal Therapy: included hormonal therapeutics but not Chemotherapy or Targeted Therapy.Data Extraction: For studies included for further review, corresponding clinicaltrials.govrecords were reviewed, and eligibility criteria extracted verbatim.If a full trial protocol was attached to the registry entry, the trial protocol was reviewed.Criteria were categorized into the mutually exclusive categories as outlined in the methods with verbatim criteria extracted for any difficult categorizations.Each study was screened and extracted independently by two reviewers.
b. Targeted Therapy: included targeted therapeutics (e.g., small molecule inhibitors, antibodies, immunomodulators) but not Chemotherapy, with or without Hormonal Therapy.c

eTable 1 .
CCT Cohort Data Extraction Template One trial excluded for lack of available eligibility criteria Trials that included more than one cancer type were included in each applicable cancer type.Proportions of Clinical Trials That Exclude Patients for ANC Values Within the DANC Reference Range by Type of Therapy and Type of Restriction Trials listed within chemotherapy are all those including cytotoxic chemotherapy (N=142), thoselisted as targeted therapy did not also test chemotherapy (N=123), those listed as hormonal therapy did not also test chemotherapy or targeted therapy (N=24).Proportions of Clinical Trials Within the US and UK That Exclude Patients for ANC Values Within the DANC Reference Range by Cancer Type and Type of Restriction Bars representing individual cancer types show all trials that include that cancer type (9 prostate, 11 melanoma, 32 breast, 11 colorectal, 50 lung), Overall Crude values are for unique trials (N=113), and Overall Weighted values weight each cancer type equally and include duplicates across cancer types (N=113).Proportions of SACT Regimens With Dose Modifications That Exclude Patients for ANC Values Within the DANC Reference Range, by Type of Therapy and Type of RestrictionRegimens listed as chemotherapy are all those including cytotoxic chemotherapy (N=44).Those listed as targeted therapy regimens do not also include chemotherapy (N=11), and those listed as hormonal therapy do not also include chemotherapy or targeted therapy (N=16).Chemotherapy and Targeted Therapy Dose Modifications That Exclude Patients for ANC Values Within the DANC Reference Range, by Cancer Type and Type of Restriction .The Overall Crude result is the sum of all regimens, and the Overall Weighted result weights equally by cancer type and then sums the results.Lung cancer (N=31), colorectal cancer (N=11), breast cancer (N=10), melanoma (N=3).Prostate cancer is not shown as all regimens identified for this cancer type were hormone-based.FDA Label-Based SACT Dose Modifications That Exclude Patients for ANC Values Within the DANC Reference Range, by Cancer Type and Type of Restriction The Overall Crude result is the sum of all regimens, and the Overall Weighted result weights equally by cancer type and then sums the results.Lung cancer (N=31), colorectal cancer (N=11), breast cancer (N=14), melanoma (N=3), prostate (N=12).