Clinical trial considerations for pediatric cancer drug development

Oncology drug discovery and development has always been an area facing many challenges. Phase 1 oncology studies are typically small, open-label, sequential studies enrolling a small sample of adult patients (i.e., 3-6 patients/cohort) in dose escalation. Pediatric evaluations typically lag behind the adult development program. The pediatric starting dose is traditionally referenced on the recommended phase 2 dose in adults with the incorporation of body size scaling. The size of the study is also small and dependent upon the prevalence of the disease in the pediatric population. Similar to adult development, the dose is escalated or de-escalated until reaching the maximum tolerated dose (MTD) that also provides desired biological activities or efficacy. The escalation steps and identification of MTD are often rule-based and do not incorporate all the available information, such as pharmacokinetic (PK), pharmacodynamic (PD), tolerability and efficacy data. Therefore, it is doubtful if the MTD approach is optimal to determine the dosage. Hence, it is important to evaluate whether there is an optimal dosage below the MTD, especially considering the emerging complexity of combination therapies and the long-term tolerability and safety of the treatments. Identification of an optimal dosage is also vital not only for adult patients but for pediatric populations as well. Dosage-finding is much more challenging for pediatric populations due to the limited patient population and differences among the pediatric age range in terms of maturation and ontogeny that could impact PK. Many sponsors defer the pediatric strategy as they are often perplexed by the challenges presented by pediatric oncology drug development (model of action relevancy to pediatric population, budget, timeline and regulatory requirements). This leads to a limited number of approved drugs for pediatric oncology patients. This review article provides the current regulatory landscape, incentives and how they impact pediatric drug discovery and development. We also consider different pediatric cancers and potential clinical trial challenges/opportunities when designing pediatric clinical trials. An outline of how quantitative methods such as pharmacometrics/modelling & simulation can support the dosage-finding and justification is also included. Finally, we provide some reflections that we consider helpful to accelerate pediatric drug discovery and development.

The incidence of pediatric drugs poses unique challenges due to the distinct corporal, pharmacokinetic, and pharmacodynamic characteristics of juveniles. Innovative methods are being developed to address these challenges and ensure the safety and efficacy of pediatric treatments. This paper investigates various approaches to improve pediatric drug handling, including the implementation of age-appropriate formulations, the use of advanced drug delivery systems, and the incorporation of real-world evidence and patient-centric models in clinical trials. Additionally, regulatory frameworks and procedures that support pediatric drug development are examined, emphasizing the roles of initiatives such as the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) in the United States, as well as similar efforts in Europe and other regions. Emphasis is placed on collaborative efforts among key stakeholders: manufacturers, academia, regulatory bodies, and patient advocacy groups, to promote change and address unmet medical needs in pediatric populations. Furthermore, this paper discusses the potential of emerging technologies, particularly artificial intelligence and genomics, to transform pediatric drug development. By leveraging these innovative strategies, the pharmaceutical industry can enhance treatment outcomes for children and advance pediatric healthcare.

More Efficient Compliance with European Medicines Agency and Food and Drug Administration Regulations for Pediatric Oncology Drug Development: Problems and Solutions

ABSTRACTTreatment abandonment is a critical issue in pediatric oncology that significantly impacts patient outcomes and survival rates. This study investigates the prevalence and factors contributing to treatment abandonment among pediatric solid cancer patients. A comprehensive literature review was conducted to explore the cultural, socioeconomic, and healthcare system-related factors influencing treatment abandonment in this population. Data was collected from 148 pediatric pediatric cancer patients diagnosed with Brain tumors in National Cancer institute, Cairo University over a 2 year period. The study also examines the implications of treatment abandonment on disease progression, patient prognosis, and overall healthcare burden. RESULTSThe study found that 14 % of pediatric Brain tumors ‘patients at our institute experienced treatment abandonment during their course of care. Factors contributing to treatment abandonment included financial constraints (34 %), lack of awareness about the importance of treatment adherence (26 %), distance to healthcare facilities (20%), and cultural beliefs (20). The impact of treatment abandonment on disease progression and patient outcomes was substantial, with [58 % p value <0.01}. By understanding the complex factors contributing to treatment abandonment in Egyptian pediatric cancer patients, healthcare providers and policymakers can implement targeted interventions to improve treatment adherence, enhance patient outcomes, and reduce the burden of pediatric cancer in Egypt.

Febrile neutropenia (FN) is a common condition in children receiving chemotherapy. Our goal in this study was to develop a model for predicting blood stream infection (BSI) and transfer to intensive care (TIC) at time of presentation in pediatric cancer patients with FN. We conducted an observational cohort analysis of pediatric and adolescent cancer patients younger than 24 years admitted for fever and chemotherapy-induced neutropenia over a 7-year period. We excluded stem cell transplant recipients who developed FN after transplant and febrile non-neutropenic episodes. The primary outcome was onset of BSI, as determined by positive blood culture within 7 days of onset of FN. The secondary outcome was transfer to intensive care (TIC) within 14 days of FN onset. Predictor variables include demographics, clinical, and laboratory measures on initial presentation for FN. Data were divided into independent derivation (2009–2014) and prospective validation (2015–2016) cohorts. Prediction models were built for both outcomes using logistic regression and random forest and compared with Hakim model. Performance was assessed using area under the receiver operating characteristic curve (AUC) metrics. A total of 505 FN episodes (FNEs) were identified in 230 patients. BSI was diagnosed in 106 (21%) and TIC occurred in 56 (10.6%) episodes. The most common oncologic diagnosis with FN was acute lymphoblastic leukemia (ALL), and the highest rate of BSI was in patients with AML. Patients who had BSI had higher maximum temperature, higher rates of prior BSI and higher incidence of hypotension at time of presentation compared with patients who did not have BSI. FN patients who were transferred to the intensive care (TIC) had higher temperature and higher incidence of hypotension at presentation compared to FN patients who didn’t have TIC. We compared 3 models: (1) random forest (2) logistic regression and (3) Hakim model. The areas under the curve for BSI prediction were (0.79, 0.65, and 0.64, P < 0.05) for models 1, 2, and 3, respectively. And for TIC prediction were (0.88, 0.76, and 0.65, P < 0.05) respectively. The random forest model demonstrated higher accuracy in predicting BSI and TIC and showed a negative predictive value (NPV) of 0.91 and 0.97 for BSI and TIC respectively at the best cutoff point as determined by Youden’s Index. Likelihood ratios (LRs) (post-test probability) for RF model have potential utility of identifying low risk for BSI and TIC (0.24 and 0.12) and high-risk patients (3.5 and 6.8) respectively. Our prediction model has a very good diagnostic performance in clinical practices for both BSI and TIC in FN patients at the time of presentation. The model can be used to identify a group of individuals at low risk for BSI who may benefit from early discharge and reduced length of stay, also it can identify FN patients at high risk of complications who might benefit from more intensive therapies at presentation.

SummaryCancer remains the leading cause of death from disease among children beyond the age of one. Survival of pediatric patients with cancer has dramatically improved over the last decades but some tumors remain almost intractable and relapse is still associated with an infaust prognosis. Despite the heterogeneity of pediatric malignancies, most treatments include the same set of generic therapies. Optimizing delivery of conventional therapeutics has been the driving force behind continuous improvements but further escalation of conventional therapy is unlikely to improve outcomes. The limited success of targeted drugs in pediatric cancer patients, originally developed for cancers in adults, can be connected to the different etiology of tumors in children versus adults. In addition, many pediatric cancers lack reliable biomarkers, cannot be studied in large cohorts and only few available therapies target abberations specific for certain pediatric cancers.These observations have led to the establishment of pediatric precision-medicine programs. The major goal of these programs is to identify patient-tailored molecular treatment plans that will eventually improve quality of life and survival. Despite the initial euphemism, the impact of actionable matched treatments and the most adequate value-based genomics strategies are not yet well established. A non-competitive collaborative model based on pediatric cancer priorities and strong collaboration between academia, pharmaceutical companies and regulators is needed. In the near future, clinical trials need to focus on biologically defined patient subsets, in an even smaller patient population. A major collaborative effort between all associated groups will be necessary to ensure success of pediatric precision cancer medicine.

This is a tremendous honor to receive peer recognition carrying the name of late Dr Sumner Yaffe. I was fortunate to have worked with him over many years through professional organizations and as a part of the pediatric pharmacology research units (PPRUs). Dr Yaffe established pediatric pharmacology programs in Buffalo and Philadelphia and made important contributions to enhance pediatric care with his research, practice, and teaching. He led the development of PPRUs and the neonatal networks, and was a force behind the framing of what became the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA). He was indeed a visionary leader and mentor in the field of pediatric pharmacology. The objectives of my presentation today are to briefly share my background, reflect on our work, and discuss potential opportunities to advance pediatric pharmacy, pharmacology, and therapeutics.

To assess the prognostic role of different inflammatory indices on the outcome of cancer patients with COVID-19. Sixty-two adults and 22 pediatric cancer patients with COVID-19 infection were assessed for the prognostic value of certain inflammatory indices including the neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), derived NLR (dNLR), systemic inflammation index (SII), mean platelet volume to platelet ratio (MPR), C-reactive protein to lymphocyte ratio (CRP/L), aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), and neutrophil to lymphocyte, platelet ratio (NLPR). Data were correlated to patients’ outcome regarding ICU admission, and incidence of mortality. Increased CRP/L ratio in adult COVID-19 cancer patients was significantly associated with inferior survival [152 (19–2253) in non-survivors, compared to 27.4 (0.8–681) in survivors (P = 0.033)]. It achieved a sensitivity (60%) and a specificity (90.2%) at a cut-off 152, while it achieved a sensitivity of 60% and specificity 95.1% at a cut-off 252 (AUC 0.795, P = 0.033). When combining both CRP/L and NLPR for the prediction of poor outcome in adult cancer patients with COVID19, the sensitivity increased to 80% and the specificity was 70.7% (AUC 0.805, P = 0.027). Increased incidence of ICU admission in pediatric cancer patients associated significantly with the severity of covid19 infection, decreased mean corpuscular hemoglobin (MCH) < 28.3, increased red cell distribution width (RDW) > 16, lymphopenia < 1.04, pseudo Pelger-Huet appearance, and PLR < 196.4 (P = 0.004, P = 0.040, P = 0.029, P = 0. 0.039, P = 0.050, and P = 0.040; respectively). The mean corpuscular volume (MCV), MCH, and RDW could be useful prognostic markers for poor outcome in COVID-19 pediatric cancer patients (P < 0.05 for all). Increased both CRP/L and NLPR associated significantly with poor survival in adult COVID-19 cancer patients, while PLR associated significantly with ICU admission in pediatric COVID-19 cancer patients.

Introduction: Cancer is a leading cause of death in childhood. Encouraging progress has been made in the treatment of childhood malignancies, but there is an unmet need for new drugs to improve survival and reduce treatment-associated toxicities. Drug development in paediatric oncology has specific requirements with regard to the patient population and the regulatory background and presents several unique challenges that need addressing.Areas covered: This review discusses the current framework of paediatric oncology drug development and some of the specific challenges in pre-clinical and clinical research. The authors discuss the recent developments in the targeting of various signalling pathways. These pathways represent a selection of targets that have been identified by pre-clinical and clinical investigators to be highly relevant in paediatric malignancies.Expert opinion: The development of targeted agents in paediatric oncology must be driven by knowledge of tumour biology. Predictive and pharmacodynamic biomarkers should be incorporated within paediatric early clinical trials wherever possible. Faster dose-escalation, limited numbers of cohorts and novel adaptive designs can help to make paediatric early clinical trials more efficient. Close collaboration between academic/clinical researchers, the pharmaceutical industry, regulatory bodies and parent groups are crucial in overcoming the challenges associated with paediatric oncology drug development.

Thirty years ago, Dr Harry Shirkey recognized the serious dilemma of pediatric drug labeling, called therapeutic orphan, to capture its concept, and described remedial measures to minimize the dilemma. This review offers a brief exposition of the therapeutic orphan's arduous journey toward the goal of labeling of all drugs used for children. Aside from legal and US Food and Drug Administration (FDA) policy requirements to secure new drug application approval to market a drug, some may question reasons for a pediatric drug label, especially if a label exists for adult use and pediatric use information is distributed in literature reports. Major pragmatic reasons for a pediatric label are presented in Table 1. A label testifies to carefully reviewed clinical trial data that offer substantial evidence to support pediatric indications for which the drug has approved use. Perhaps of unappreciated importance is availability of information on the label. Time-consuming literature review and analysis often are not necessary when a pediatric label exists. Label information is compiled for the pediatric drug formulation, and it is this formulation that is approved. Literature reports often contain one or more formulations prepared by the investigator, and good manufacturing procedures or bioavailability estimates may be less than desired. A formulation on the label frequently has been evaluated for characteristics acceptable to children and hence compliance is strengthened. The drug, having met pediatric labeling requirements, is available for children and obviates the awkward double standard—one for adults (label necessary for marketing) and one for children (pediatric label not necessary for marketing or use). To the lay public, this pediatric labeling allows third-party reimbursement of drug costs otherwise denied. This relieves young parents of a truly indefensible economic burden, which in some cases has denied drug treatment to children. Add to this the refusal of some malpractice … Address correspondence to John T. Wilson, MD, Section on Clinical Pharmacology, Department of Pediatrics, Louisiana State University Medical Center, Shreveport, LA 71130.

Pediatric cancer treatment includes several chemotherapeutic drugs in combination with adequate supportive management. Symptom distress among pediatric cancer patients on chemotherapy interferes with treatment compliance. Poorly managed distress leads to the decline of the child’s ability physically and mentally and deteriorates the quality of life. This paper shows the effect of chemotherapeutic drugs induced symptom distress, and the effect of early diagnosis in the management and improvement in the quality of life of pediatric cancer patients. For this study60, pediatric cancer patients aged between 10 to 18 years including both the gender were chosen using purposive sampling. Using the M.D. Anderson symptom inventory the symptom distress experienced by the pediatric cancer patients was assessed. The present quantitative cross-sectional study was conducted at the AIIMS, Raipur. The data were analyzed using the descriptive Statistical Package for Social Science Version 16 (SPSS 16). The categorical data was analyzed using chi –square test and the cut off p-value at ≤0.05. Among, the pediatric cancer patients 77.65% (SD 18.85) were experiencing severe symptom distress when on chemotherapy. Whereas 53.65 %( SD 9.63). of them experiencing the symptoms those disturb their activities of daily living in the last twenty four hours at p-value of ≤0.05. There is a need for an adequate support system from the school, social relationship, siblings, and health care team for improving the quality of life of pediatric cancer patients. Animal facilitated therapy, artistics expressions, medical play, procedural education, well organized home bound or school programs help the pediatric cancer patients to manage the symptom distress, thereby improving the treatment outcome. The specific supportive chemotherapeutic management is essential for the pediatric cancer patient’s treatment compliance and prognosis. The health care team, especially nurses play a vital role in early detection of chemotherapeutic agents induced symptom distress and its management.

Advancements in treatment, along with enhanced supportive care have led to rates of survival among pediatric cancer patients. 1)Every year the States, approximately 15,000 children between the ages of 0 and 19 are diagnosed with cancer, with over 85% surviving for at least 5 years.2) The majority of patients experience long-term survival, with over 500,000 in the United States and 30,000 in Korea. 2,3)However, childhood cancer survivors undergo the long-term complications including endocrine disorders commonly.Endocrine complications encompass growth failure, hypopituitarism, hypogonadism, hypothyroidism, diabetes mellitus, dyslipidemia, obesity, osteoporosis, adrenal insufficiency. 2,4)A systematic review from 3 studies revealed that around 29.0% to 39.1% of childhood cancer survivors treated with cranial radiation therapy experienced growth hormone deficiency, with higher doses of cranial radiation associated with a higher risk. 5)Shin et al. 6) reported a oneyear effect of growth hormone replacement without recurrence or occurrence of other tumors in 19 out of 24 growth hormone deficiency patients who survived childhood leukemia.Childhood cancer survivors demonstrate decreased bone mineral density (BMD) relative to the general population, which can be attributed not only to chemotherapeutic treatments like glucocorticoids and radiation but also to factors like the cancer itself, hormonal insufficiency, inadequate nutrition, and reduced physical activity. 7,8)Jang et al. 9) emphasized the importance of evaluating BMD and monitoring the cumulative dose and duration of glucocorticoids for patients with secondary osteoporosis.According to clinical practical guidelines for optimizing bone health in Korean children and adolescents, sufficient intake of calcium and vitamin D, along with adequate body weight and physical activity, are recommended for childhood cancer survivors.Bisphosphates could also be helpful in increasing BMD. 10) The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group 11) recommend counseling female childhood, adolescent, and young adult cancer patients who are at potential risk of infertility due to high-dose alkylating agents, ovarian radiotherapy, or hematopoietic stem cell transplantation (HSCT) about fertility preservation options such as oocyte or embryo cryopreservation and harvesting of ovarian tissue for cryopreservation. 12)Before undergoing gonadotoxic chemotherapy or radiotherapy, testicular tissue cryopreservation is primarily offered to young male cancer patients.Moreover, Delgouffe et al. 13) recommend testicular tissue banking for male patients requiring high-risk conditioning therapy before HSCT or bone marrow transplantation.In this research, 14) the authors studied 200 Korean childhood cancer survivors after HSCT and revealed that 67.5% of the patients experienced endocrine complications.Short stature and diabetes mellitus were prevalent among the prepubertal HSCT group, while hypogonadism and osteoporosis were more common among the pubertal HSCT group. 14)Factors such as pubertal age at HSCT, female sex, and steroid use were identified as predictors of increased risk of endocrine complications.Another retrospective study from Spain involving 157 children post-HSCT presented similar risk factors for endocrinopathies including older age at HSCT, pubertal Tanner stage V, chronic graft-vs-host disease, direct gonadal therapy and specific treatments such as radiotherapy and steroids. 15)Figueiredo et al. 16) also reported similar results from a study of 152 Portuguese patients after HSCT during childhood.We need to plan

Context: Despite recombinant factor VIIa (rFVIIa) being approved for treating bleeding in hemophilia patients, there has been limited research on its efficacy in nonhemophilic cases, particularly, in pediatric cancer patients who are vulnerable to bleeding. Aim: Our objective is to assess rFVIIa’s effectiveness in managing severe bleeding in pediatric nonhemophilic cancer patients. Settings and Design: We conducted a retrospective study at a comprehensive cancer center. Materials and Methods: It involves reviewing cases of nonhemophilic pediatric cancer patients treated with rFVIIa for acute severe bleeding during hospitalization between 2013 and 2022 using the pharmacy electronic system. Patients without a cancer diagnosis were excluded. The primary outcome assessed was the cessation of bleeding within 48 h post the last administered rFVIIa dose. Statistical Analysis Used: Descriptive statistics were used to report the outcomes. Results: The results revealed that our analysis encompassed 22 nonhemophilic pediatric cancer patients experiencing acute severe bleeding. The mean age was 7 ± 16.9 (SD) years, with 18 (81.8%) being male. Among them, 7 (31.8%) had leukemia and 5 (22.7%) had neuroblastoma. Thrombocytopenia was prevalent in 21 (95.5%) patients, and 7 (31.8%) underwent bone marrow transplantation. On average, patients received 85 ± 10 (SD) µg/kg of rFVIIa for one to two doses per bleeding episode. Bleeding cessation was achieved in 13 (59%) patients. Conclusion: Our findings suggest that rFVIIa could serve as a viable therapeutic option for managing acute severe bleeding in nonhemophilic pediatric cancer patients.

Central nervous system (CNS) tumors are the second common pediatric malignancies, accounting for approximately 25% of all childhood neoplasms. Cerebrospinal fluid (CSF) is a very valuable source of biomarkers for brain tumors and represents a potential indicator of pathological processes that happen in the CNS. CSF biomarker discovery poses some physiological and technical challenges: low protein levels (total protein concentration 0.3 to 0.7 mg/mL), dynamic range (up to approximately 12 order of magnitude), and the presence of highly abundant proteins masking the less abundant ones. In order to overcome these challenges, we used core-shell capturing hydrogel nanoparticles that can capture, preserve and concentrate candidate low molecular weight, low abundance proteins in solution in one step improving the effective sensitivity of mass-spectrometry by several orders of magnitude. CSF samples from pediatric brain cancer patients (14 medulloblastoma, 4 high-grade glioma, 6 ependimoma, 4 PNET, 2 atypical teratoid rhabdoid tumor) either at initial diagnosis (n=27) or at tumor recurrence (n=3) and 21 non-brain pediatric oncology controls (extra-CNS non Hodgkin lymphoma) were processed with core-shell hydrogel nanoparticles and then analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (MS/MS). We identified 559 non redundant proteins, 147 (26%) of those not present in the public comprehensive CSF proteome database (www.biosino.org). Functional classification analysis performed with IPA Ingenuity System showed that CSF contained proteins normally involved in neurological diseases, developmental disorders, cellular movement, cellular growth and proliferation. Several candidate proteins that show a statistical difference (p-value &amp;lt;0.05, Fisher test) between brain tumor and non-brain oncology controls, were involved in the process of extracellular matrix (ECM) remodeling which has a key role in the transition to invasive cancer and is often an indicator of worse prognosis. Two examples were a) the ECM protein collagen XVIII, which was previously identified in meningioma tissue with a fast progression, and b) procollagen C-endopeptidase enhancer, an extracellular matrix glycoprotein related to tumor growth and angiogenesis. Statistical analysis between non-metastatic and metastatic patient samples also highlighted potentially relevant proteins such as GDNF family receptor α-2 (GFRα2); two other family members GFRα1 and GFRα3 were reported to have a role in tumor growth and invasiveness. In conclusion, combining a unique dataset of CSF from pediatric cancer patients with a novel enabling nanotechnology allowed us to identify important insights for diagnosis, prognosis and molecular stratification of CNS pediatric tumors. Citation Format: Ruben Magni, Paolo Verderio, Lance Liotta, Filippo Spreafico, Maura Massimino, Alessandra Luchini, Italia Bongarzone. Investigation of the cerebrospinal fluid proteome from central nervous system pediatric tumors using bait loaded hydrogel nanoparticles and mass spectrometry. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1874. doi:10.1158/1538-7445.AM2014-1874

High throughput next generation sequencing (NGS) has enabled tremendous advances in our understanding of the genomic landscape of pediatric cancer, leading to discoveries of new mechanisms of tumor initiation and progression, novel targets, and diagnostic and prognostic markers. By focusing on the development of innovative computational analysis tools, we have investigated the genomic variants in pediatric cancer in the following areas: 1) genomic landscapes of &amp;gt;20 subtypes of pediatric cancer; 2) a pan-cancer study of genomes and transcriptomes of pediatric cancer which unveiled that &amp;gt;50% of the driver genes are absent in adult cancer; 3) clonal evolution of relapsed pediatric leukemia driven by therapy-induced variants bearing novel mutational signature; and 4) pathogenic germline mutations in cancer predisposition genes. These insights led to implementation of clinical cancer genomic profiling by three-platform of whole genome, whole exome and transcriptome sequencing for all eligible pediatric cancer patients at St Jude. Use of these data sets improved molecular diagnosis of pediatric cancer. Since 2015, we have analyzed &amp;gt;1,200 pediatric oncology patients providing critical data that may affect patient care. The omics data generated from our research and clinical programs can be accessed on St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem for accessing, analyzing and visualizing genomic data generated from &amp;gt;10,000 pediatric cancer patients, long-term survivors of pediatric cancer and &amp;gt;800 pediatric sickle cell patients. Access to three interconnected Apps on St. Jude Cloud, i.e. Genomics Platform, Pediatric Cancer (PeCan) Knowledgebase and Visualization Community, provides a unique experience for simultaneously performing advanced data analysis and enhancing the knowledgebase for pediatric cancer. Citation Format: Jinghui Zhang. Big pediatric cancer genomic data: Discovery, precision medicine, and data sharing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-18.