National Cancer Institute Clinical Trials Research Articles

The National Cancer Institute Clinical Trials Planning Meeting to Address Gaps in Observational and Intervention Trials for Cancer-Related Cognitive Impairment

Abstract Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein.

Increasing diversity in clinical trials: demographic trends at the National Cancer Institute, 2005-2020.

We described participant demographics for National Cancer Institute (NCI) clinical trials at the clinical center (NCI-CC participants) of the National Institutes of Health to identify enrollment disparities. We analyzed NCI-CC data from 2005 to 2020, calculated enrollment fractions, compared with the US cancer population represented by the Surveillance, Epidemiology, and End Results cancer incidence data (2018) and the Cancer in North America database (2018), and compared further with clinical trial disparities data from the NCI Community Oncology Research Program and National Clinical Trials Network (2005-2019), and from ClinicalTrials.gov (2003-2016). NCI-CC (38 531 participants) had higher enrollment fractions for older adults (8.5%), male (5.6%), non-Hispanic (5.1%), and Black or African American (5.3%) participants; lower women proportion across race and ethnicity; and fewer female sex-specific cancer (6.8%) than male sex-specific cancer (11.7%) participants. NCI-CC had lower median age than Surveillance, Epidemiology, and End Results (54.0 vs 65.4); more Black or African American participants (12.0% vs 11.1%); and fewer women (41.7% vs 49.5%), White (76.1% vs 80.5%), Asian or Pacific Islander (4.6% vs 6.0%), American Indian or Alaska Native (0.3% vs 0.5%), and Hispanic participants (7.1% vs 13%). NCI-CC had more Black or African American and Asian or Pacific Islander participants; fewer Hispanic participants than the NCI Community Oncology Research Program and National Clinical Trials Network; more Black or African American and Hispanic participants; fewer Asian or Pacific Islander participants than ClinicalTrials.gov data. Improvement was noted for NCI-CC (older adults, Black or African American, Asian or Pacific Islander, Hispanic participants). We found lower representation of older adults, women, Asian or Pacific Islander, American Indian or Alaska Native, and Hispanic participants vs the US cancer population and higher representation of Black or African American vs US cancer population and oncology clinical trials. Multifaceted efforts are underway to reduce disparities in cancer clinical trials at the NCI-CC.

A novel GATA2 distal enhancer mutation results in MonoMAC syndrome in 2 second cousins

AbstractMutations in the transcription factor GATA2 can cause MonoMAC syndrome, a GATA2 deficiency disease characterized by several findings, including disseminated nontuberculous mycobacterial infections, severe deficiencies of monocytes, natural killer cells, and B lymphocytes, and myelodysplastic syndrome. GATA2 mutations are found in ∼90% of patients with a GATA2 deficiency phenotype and are largely missense mutations in the conserved second zinc-finger domain. Mutations in an intron 5 regulatory enhancer element are also well described in GATA2 deficiency. Here, we present a multigeneration kindred with the clinical features of GATA2 deficiency but lacking an apparent GATA2 mutation. Whole genome sequencing revealed a unique adenine-to-thymine variant in the GATA2 –110 enhancer 116,855 bp upstream of the GATA2 ATG start site. The mutation creates a new E-box consensus in position with an existing GATA-box to generate a new hematopoietic regulatory composite element. The mutation segregates with the disease in several generations of the family. Cell type–specific allelic imbalance of GATA2 expression was observed in the bone marrow of a patient with higher expression from the mutant-linked allele. Allele-specific overexpression of GATA2 was observed in CRISPR/Cas9-modified HL-60 cells and in luciferase assays with the enhancer mutation. This study demonstrates overexpression of GATA2 resulting from a single nucleotide change in an upstream enhancer element in patients with MonoMAC syndrome. Patients in this study were enrolled in the National Institute of Allergy and Infectious Diseases clinical trial and the National Cancer Institute clinical trial (both trials were registered at www.clinicaltrials.gov as #NCT01905826 and #NCT01861106, respectively).

Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy.

Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy.

Trial Design Considerations to Increase Older Adult Accrual to National Cancer Institute Clinical Trials.

Although adults aged 65 years or older make up a strong majority of cancer patients, their underrepresentation in cancer clinical trials leads to the lack of representative data to guide evidence-based therapeutic decisions in this patient population. The Trial Design Working Group, convened as part of the workshop titled, Engaging Older Adults in the National Cancer Institute Clinical Trials Network: Challenges and Opportunities, recommended study designs and design elements that could improve accrual of older adults in National Cancer Institute-funded clinical trials. These include trials that are specifically designed to enroll older adults, trials that include a cohort of older patients (parallel cohort, stratified cohort, or embedded cohort), and trials with pragmatic design elements to facilitate enrollment of older adults. This manuscript provides brief descriptions of the recommended designs, examples of successful trials, and considerations for implementation of these designs. As with any clinical trial, the scientific questions and trial objectives should drive the study design, the selection of endpoints and intervention, and eligibility criteria. When designing trials that include older adults, the heterogeneity of fitness levels is an important consideration as fitness can influence accrual rates and outcomes. Appropriately incorporating geriatric assessments can help identify the optimal subset of older patients for inclusion and minimize selection bias. Incorporating pragmatic design elements to reduce the burden on trial participants as well as on accruing sites and retaining essential elements to ensure that the main goal of the trial can be accomplished can enhance enrollment without compromising the integrity of trials.

Integrating Geriatric Assessment Measures into National Cancer Institute Clinical Trials.

To improve the care of older adults with cancer, the traditional approach to clinical trial design needs to be reconsidered. Older adults are underrepresented in clinical trials with limited or no information on geriatric-specific factors, such as cognition or comorbidities. To address this knowledge gap and increase relevance of therapeutic clinical trial results to the real-life population, integration of aspects relevant to older adults is needed in oncology clinical trials. Geriatric assessment (GA) is a multidimensional tool comprising validated measures assessing specific health domains that are more frequently affected in older adults, including aspects related to physical function, comorbidity, medication use (polypharmacy), cognitive and psychological status, social support, and nutritional status. There are several mechanisms for incorporating either the full GA or specific GA measures into oncology therapeutic clinical trials to contribute to the overarching goal of the trial. Mechanisms include utilizing GA measures to better characterize the trial population, define trial eligibility, allocate treatment receipt within the context of the trial, develop predictive models for treatment outcomes, guide supportive care strategies, personalize care delivery, and assess longitudinal changes in GA domains. The objective of this manuscript is to review how GA measures can contribute to the overall goal of a clinical trial, to provide a framework to guide the selection and integration of GA measures into clinical trial design, and ultimately enable accrual of older adults to clinical trials by facilitating the design of trials tailored to older adults treated in clinical practice.

Preface: Engaging Older Adults in Cancer Clinical Trials Conducted in the National Cancer Institute Clinical Trials Network: Opportunities to Enhance Accrual

Preface: Engaging Older Adults in Cancer Clinical Trials Conducted in the National Cancer Institute Clinical Trials Network: Opportunities to Enhance Accrual

Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials.

As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials.

Through the Lens of Patient Partners: Challenges in Accrual of Older Adults to NCI Clinical Trials.

The workshop "Engaging Older Adults in Cancer Clinical Trials Conducted in the NCI Clinical Trials Network: Challenges and Opportunities" included a Patient Stakeholder Workgroup that explored the needs and concerns of older adults with cancer regarding clinical trials. To accomplish this, the workgroup conducted patient focus groups in which participants were interviewed, recorded conversations were analyzed and coded, and salient themes were identified. The focus groups identified general barriers to accrual such as complex consent forms, general communication, restrictive eligibility, nonreferrals, patient costs, cultural insensitivity, limited accessibility in community settings, and transportation issues. They also identified the influence of knowledgeable information presenters, improved care, family or caregiver support, and the desire to help others as drivers or reasons to participate in clinical trials. The workshop concluded that multi-level interventions could be used to increase the accrual of older adults to National Cancer Institute clinical trials as well as others.

Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting.

International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. A National Cancer Institute-sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma.

Implementing Modernized Eligibility Criteria in US National Cancer Institute Clinical Trials.

In 2018, the Cancer Therapy Evaluation Program (CTEP) at the US National Cancer Institute published new protocol template language that focused on organ function and prior and concurrent cancers in an effort to modernize eligibility criteria for cancer treatment trials. We conducted an analysis of CTEP-supported trials to evaluate the uptake and incorporation of the new language. The analysis included evaluation of 122 protocols approved in the years 2018-2020 for inclusion of the modernized eligibility criteria and consistency with new protocol template language related to 7 major eligibility criteria. These were cardiac function, liver function, kidney function, HIV status, prior and/or concurrent malignancies, treated and/or stable brain metastasis, and new and/or progressive brain metastases. Overall, CTEP trials evaluated in this period demonstrated that eligibility criteria were implemented to a relatively high degree ranging from a low of 54.1% for prior and/or concurrent malignancies to a high of 93.4% for eligibility criteria related to HIV infection. The findings demonstrate that modernized eligibility criteria can be successfully implemented but that consistent implementation requires sustained focused effort. As a result of these findings, CTEP began a new initiative in January 2022 that incorporates a specific review of eligibility criteria for new protocols to promote and improve consistency with the modernization effort.

Improving Patient Advocacy in NCI Scientific Steering Committees and Task Forces.

This commentary discusses improving research advocacy as part of National Cancer Institute (NCI) clinical trial activities in scientific steering committees and task forces between 2016 and 2020. Before 2016, the focus of patient advocate input on clinical trial concept evaluation was assessing accrual feasibility. By leveraging informal benchmarking and an outside-in perspective, the NCI patient advocate steering committee, comprised of NCI scientific steering committee and task force advocates, has recalibrated research advocacy within and across its clinical trial concepts. Additionally, by focusing on research advocacy fundamentals, the NCI patient advocate steering committee clarified the scope of the research advocate roles, focused its mission, defined and developed competencies, measured engagement, and created collateral and processes that support better interactions and greater value generation. Continuous improvement in the collateral and the underlying approaches, along with calibrating their application and monitoring results, will be necessary to keep pace with the science and further enhance the value of cancer clinical trial research advocacy. The road ahead should build on these fundamentals and include increased emphasis on diversity, equity, and inclusion in clinical trial and research advocacy participants and the supporting infrastructure.

Patterns of Enrollment in Cancer Treatment Trials During the COVID-19 Pandemic at National Cancer Institute-Designated Cancer Centers.

The COVID-19 pandemic posed unprecedented strain on enrollment to cancer clinical trials and their conduct. Here, we highlight an analysis using information from the National Cancer Institute (NCI) Clinical Trials Reporting Program database to describe enrollment patterns to interventional cancer treatment trials at NCI-Designated Cancer Centers during the pandemic. Enrollment to cancer treatment trials at NCI-Designated Cancer Centers decreased precipitously early in the pandemic and has not yet fully returned to the 2019 baseline as of mid-2021. We discuss possible reasons for this and how some of the changes in clinical trial conduct implemented during the pandemic may become part of the standard conduct of NCI-supported clinical trials and broaden access to trials.

Comparison of Design, Eligibility, and Outcomes of Neuroendocrine Neoplasm Trials Initiated From 2000 to 2009 vs 2010 to 2020

Neuroendocrine neoplasms (NENs) have historically been grouped homogenously in clinical trials, despite their heterogeneity. Given the adoption of a more advanced pathologic classification system and drug licensure of several targeted therapies over the last decade, information is needed on whether study characteristics of NEN studies have evolved. To assess changes in study design, eligibility, accrual, sponsorship, and outcomes between phase II or III NEN clinical trials that began enrollment from 2000 to 2009 vs 2010 to 2020. This quality improvement study used a systematic survey of completed studies published between January 1, 2000, and December 31, 2020. Therapeutic phase II and III NEN studies were identified through a database search of Medline (via PubMed), EMBASE (OvidSP), Cumulative Index of Nursing and Allied Health Literature (EBSCOhost), Web of Science (Clarivate), Cochrane Database of Systematic Reviews (Wiley), ClinicalTrials.gov (National Institutes of Health), EU Clinical Trials Register, and National Cancer Institute Clinical Trials. Data were analyzed between March and June 2021. Study characteristic proportions between the 2 enrollment periods. Of 3243 identified studies, 119 studies met criteria for inclusion, of which 117 studies (54 studies that began enrollment between 2000-2009 and 63 studies that began enrollment between 2010-2020) included exact dates of enrollment and were compared. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were less likely to include all NENs (13 studies [21%] vs 34 studies [63%]; P < .001) and more likely to include select NENs (eg, gastrointestinal neuroendocrine tumors, 25 studies [40%] vs 11 studies [20%]; P = .02; pancreatic neuroendocrine tumors, 32 studies [51%] vs 16 studies [30%]; P = .02). Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to specify tumor differentiation (59 studies [98%] vs 34 studies [63%]; P < .001) or Ki-67 index (23 studies [38%] vs 5 studies [9%]; P < .001) in inclusion criteria. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to use progression-free survival (22 studies [35%] vs 9 studies [18%]; P = .04) rather than objective response rate (19 studies [30%] vs 27 studies [53%]; P = .01) as a primary or coprimary end point. These findings suggest that NEN trials enrolling over the last decade were more focused on select tumor populations, compared with studies that began enrollment before 2010. Despite this shift, more than 20% of studies still included all NENs. Studying novel agents in specific disease populations may enhance drug development in the field.

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Phase 0 Radiopharmaceutical-Agent Clinical Development.

The evaluation of antibody-targeted or peptide-targeted radiopharmaceuticals as monotherapy or in oncological drug combinations requires programmatic collaboration within the National Cancer Institute (NCI) clinical trial enterprise. Phase 0 trials provide a flexible research platform for the study of radiopharmaceutical–drug pharmacokinetics, radiation dosimetry, biomarkers of DNA damage response modulation, and pharmacodynamic benchmarks predictive of therapeutic success. In this article, we discuss a phase 0 clinical development approach for human antibody-targeted or peptide-targeted radiopharmaceutical–agent combinations. We expect that early-phase radiopharmaceutical–agent combination trials will become a more tactical and more prevalent part of radiopharmaceutical clinical development in the near-term future for the NCI Cancer Therapy Evaluation Program.

National Cancer Institute: Restructuring to Support the Clinical Trials of the Future.

To describe the evolution and structure of the National Cancer Institute clinical trials programs, their notable accomplishments, nurses' roles in these accomplishments, and the essential role of nursing today and in the future. Manuscripts, government publications, websites, and professional communications. Change is inevitable and a constant factor in the world of advancing science and clinical research. Nurses' contribution to research and evidence-based practice will continue to grow and is vital as the scientific landscape evolves. As the understanding of cancer biology increases and clinical trials evolve, nurses will need to remain key team members and leaders in National Cancer Institute Community Oncology Research Program and National Cancer Trials Network trials and their associated infrastructure.

Toward Improving Practices for Submission of Diagnostic Tissue Blocks for National Cancer Institute Clinical Trials.

The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology. The NCI convened a 1-day workshop of multidisciplined experts to discuss barriers and strategic solutions to facilitate diagnostic block submission for clinical trial science, from the perspective of patient advocates, legal experts, pathologists, and clinical oncologists. The expert views and opinions were carefully noted and reported. Recommendations were proposed to reduce institutional barriers and to assist organizations in developing clear policies regarding diagnostic block submission for clinical trials.

Association of National Cancer Institute–Sponsored Clinical Trial Network Group Studies With Guideline Care and New Drug Indications

National Cancer Institute Clinical Trial Network (NCTN) groups serve a vital role in identifying effective new antineoplastic regimens. However, the downstream clinical effect of their trials has not been systematically examined. To examine the association of NCTN trials with guideline care and new drug indications. This retrospective cohort study evaluated phase 3 SWOG Cancer Research Network clinical trials from January 1, 1980, through June 30, 2017. Only completed trials with published results were included. To be considered practice influential (PI), a trial must have been associated with guideline care through its inclusion in National Comprehensive Cancer Network (NCCN) clinical guidelines or US Food and Drug Administration (FDA) new drug approvals in favor of a recommended treatment. Data were analyzed from June 15, 2018, through March 29, 2019. Estimated overall rate of PI trials, as well as trends over time. The total federal investment supporting the set of trials was also determined. In total, 182 trials consisting of 148 028 patients were studied. Eighty-two studies (45.1%; 95% CI, 37.7%-52.6%) were PI, of which 70 (38.5%) influenced NCCN guidelines, 6 (3.3%) influenced FDA new drug approvals, and 6 (3.3%) influenced both. The number of PI trials was 47 of 65 (72.3%) among those with positive findings and 35 of 117 (29.9%) among those with negative findings. Thus, 35 of 82 PI trials (42.7%) were based on studies with negative findings, with nearly half of these studies (17 of 35 [48.6%]) reaffirming standard of care compared with experimental therapy. The total federal investment spent in conducting the trials was $1.36 billion (2017 US dollars), a rate of $7.5 million per study or $16.6 million per PI trial. Nearly half of all phase 3 trials by one of the NCTN's largest groups were associated with guideline care or new drug indications, including those with positive and negative findings. Compared with the costs of a new drug approval in pharmaceutical companies, typically estimated at more than $1 billion, the amount of federal funds invested to provide this valuable evidence was modest. These results suggest that the NCTN program contributes clinically meaningful, cost-efficient evidence to guide patient care.

The impact of NCI-sponsored network group clinical trials on guideline care and new drug indications.

6604 Background: National Cancer Institute Clinical Trial Network (NCTN) groups serve a vital role in identifying new antineoplastic regimens. However, the clinical impact of their trials has not been systematically examined. We analyzed the influence of network group cancer clinical trials on clinical guidelines and new drug approvals. Methods: We evaluated Phase III cancer clinical trials which the SWOG Cancer Research Network coordinated or participated in (1980-2017). Included trials were completed and its results published. A documented practice influential (DPI) trial was one with verified influence on National Comprehensive Cancer Network (NCCN) clinical guidelines (available starting in 1996) or on U.S. Food and Drug Administration (FDA)-approved package inserts. We estimated the rate of DPI trials overall and over time. The total federal investment supporting the set of trials was also determined based on public data. Results: In total, 182 trials comprising 148,028 patients were studied. We identified 79 DPI studies (43.4%); 73 influenced NCCN guidelines, 12 influenced new drug approvals, and 6 influenced both. The rate of DPI trials was 72.3% (47/65) among formally positive trials (i.e., achieved their protocol specified endpoint) and 27.4% (32/117) among negative trials. Thus 40.5% (32/79) of DPI trials were based on negative studies, half of which (16/32 = 50.0%) reaffirmed standard of care over experimental therapy. There were no differences between DPI and non-DPI trials in key study design characteristics. Total federal investment for the programs conducting the trials was $1.36 billion (USD2017), a rate of $7.5 million per trial, or $17.2 million per DPI trial. Conclusions: Nearly half of all phase III trials by one of the NCTN’s largest groups had documented practice influence on clinical care guidelines or new drug approvals. Even many negative trials impacted guideline recommendations. Compared to the costs of a new drug approval in pharmaceutical companies – typically estimated at &gt; $1 billion – the amount invested by federal funders to provide this valuable evidence was modest. These findings highlight the major role of the NCTN’s clinical trial program in advancing oncology practice.