Roadmap for the Next Generation of Children’s Oncology Group Rhabdomyosarcoma Trials

Abstract

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group (IRSG) and Children’s Oncology Group (COG) have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, we outline the proposed strategic approach of the COG Soft Tissue Sarcoma (STS) Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.

PRECIS:

The rarity and complexity of rhabdomyosarcoma makes early and systematic planning for the next generation of Phase 3 trials essential. This Commentary reviews the Children’s Oncology Group Soft Tissue Sarcoma committee’s strategy to design and conduct of our next generation of rhabdomyosarcoma trials.

BACKGROUND

Rhabdomyosarcoma (RMS) is a rare cancer with an incidence of approximately 4.5 per million children and adolescents under 20 years of age.^1,2 Due to its rarity, concerted international efforts to improve outcomes for RMS, primarily through large cooperative group clinical trials, have been necessary. From 1972 to 1997, four successive Intergroup Rhabdomyosarcoma Study Group (IRSG) trials transformed the clinical approach to the diagnosis and treatment of RMS in North America by establishing the stage and group classifications and risk stratification, improving the 5-year overall survival from 55% to 71%.^3–6 The Children’s Oncology Group (COG) Soft Tissue Sarcoma (STS) committee built upon the foundation of IRSG and conducted the next iteration of clinical trials in RMS, testing various approaches for upfront and relapsed RMS treatment and further refining RMS risk stratification.^7–12 The most recently accrued and ongoing COG RMS trials, ARST1431 (NCT02567435), ARST2031 (NCT04994132), and ARST2032 (NCT05304585), test novel agents for upfront RMS treatment (vinorelbine and temsirolimus), incorporate molecular data in risk stratification and treatment allocation (FOXO1 fusion, MYOD1 and TP53 mutational status), and evaluate a reduction in therapy for a newly-defined risk subgroup, very low-risk RMS.

Despite this progress, several persistent and evolving challenges affect the ability to conduct RMS trials. First, there is a lack of novel agents with sufficient preclinical and early clinical data for incorporation into phase 3 studies for patients with newly diagnosed and/or relapsed RMS.¹³ Drug development for RMS and other pediatric cancers is hampered by several factors, including disease rarity and financial disincentives for industry development of novel agents.¹³ To improve the survival of RMS patients, we must find ways to accelerate the discovery and early-phase evaluation of promising novel agents for RMS to be expeditiously tested in phase 3 trials. Second, since the optimal care of patients with RMS requires expertise from multiple disciplines, including pediatric oncology, surgery, radiation oncology, pathology, and radiology, a framework for clinical trial development that engages all stakeholders early in trial development is crucial. Finally, while improved survival remains the desired primary objective of interest for all most clinical trials for patients with RMS, formalized investigation of treatment-related toxicities has historically not been prioritized. Efforts to accurately capture and address short and long-term treatment toxicities, especially from the perspective of trial participants, is necessary both to ensure that reduction of therapy strategies improve quality of life and to understand the toxicities of novel therapies.

Designing trials to address each of these issues will require a systematic approach. Given the anticipated completion of ongoing RMS COG trials by 2027, the COG STS committee has begun planning the strategy for future RMS studies. The RMS Clinical Trial Strategy Task Force was formed in February 2023, and its initial recommendations were presented at the 2023 COG meeting. Incorporating STS committee feedback from this meeting, we next sought expertise from numerous consultants, including clinicians (pediatric oncologists, radiation oncologists, surgeons, pathologists), researchers (basic science, translational, and clinical), and patient advocates, including stakeholders within the STS committee, stakeholders outside of STS but within COG, and external stakeholders beyond the COG network, to ensure a comprehensive approach. A summary of recommendations was presented at the 2023 Fall COG meeting and is detailed here.

When synthesizing the recommendations, our task force delineated five major domains of strategic focus for future clinical trial development (Figure 1). The focus areas are 1) building collaborations to improve novel agent identification and preclinical to clinical translation, 2) improving efficiency of trial development and implementation through new partnerships, 3) expanding opportunities for knowledge generation during the conduct of clinical trials, 4) addressing short- and long-term toxicity and quality of life through integration of patient-reported outcomes and 5) prioritizing patient engagement.

Figure 1:

Proposed strategic approach for the development and implementation of the next generation of Children’s Oncology Group rhabdomyosarcoma trials. Abbreviations: DVL: developmental therapeutics, PD: pharmacodynamics, PGx: pharmacogenomics, PIVOT: Pediatric Preclinical In Vivo Testing Progam, PK: pharmacokinetics, PROs: patient-reported outcomes, PROXC: Pediatric Research Oncology Xenografting Consortium. Figure created with BioRender.com

1). Building collaborations to improve novel agent identification and preclinical to clinical translation

Identifying novel agents for RMS may involve developing drugs specifically targeting RMS biology or identifying novel or repurposed drugs in early clinical development for other cancers with a target applicable to RMS. RMS-specific drug design remains a critical priority but this process is slow and costly. Newer technologies, such as artificial intelligence (AI) and large collaborations, may expedite this process.¹⁴ Identifying drugs under development for other cancers or drugs already approved for different indications remains a more pragmatic approach. In 2020, the COG RMS New Agents Task Force assessed new therapies with potential activity against RMS and based on the strength of published preclinical and clinical evidence, prioritized five agents from four mechanistic drug classes: DNA damage/repair, epigenetic targeting, IGF-1R inhibiting, and novel cytotoxics.¹⁵ However, there were insufficient RMS-specific preclinical data in four of five prioritized agents to support a phase 3 RMS clinical trial concept, and no study concept testing a novel agent for RMS in COG has been approved since.

The preclinical barriers to identifying and translating promising novel agents for RMS are multifaceted. They include insufficient data in clinically relevant, patient-derived ex vivo models and sparse data for properly executed efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) studies in representative animal models of RMS. Additionally, there is a scarcity of preclinical data evaluating how novel agents interact with standard agents, hindering the incorporation of new agents into existing chemotherapeutic regimens. Moreover, there are a limited number of investigators dedicated to these types of time- and resource-intensive studies in RMS. These efforts are often siloed, with data access typically occurring post-publication, resulting in a significant delay between data generation and sharing.

To address these barriers, our task force has engaged the National Cancer Institute (NCI) Pediatric Preclinical in Vivo Testing (PIVOT) Program and the Pediatric Research in Oncology Xenografting Consortium (PROXC) to pursue formal partnerships with the STS committee. NCI PIVOT is a multi-institutional program built upon nearly two decades of experience from prior NCI programs, the Pediatric Preclinical Testing Program (PPTP) and the Pediatric Preclinical Testing Consortium (PPTC), which collaborates with pharmaceutical companies to test novel agents.^16,17 NCI PIVOT systematically evaluates new drugs or combinations in vivo using genomically-characterized pediatric cancer models to accelerate potential translation into clinical investigations.¹⁸ PROXC is a multi-institutional effort that leverages a confederated collection of over 500 patient-derived xenograft (PDX) models (>70 RMS PDXs) with accompanying clinical and molecular characterization data to conduct preclinical studies utilizing a harmonized testing approach to inform drug prioritization in clinical trials. The STS committee envisions a working group consisting of scientists and clinical investigators regularly collaborating with PIVOT and PROXC to discuss new findings and access preclinical data prior to publication to guide the prioritization of agents for future study in a more timely manner. In contrast to the 2020 RMS New Agents Task Force, this new working group will support ongoing reciprocal collaboration between basic scientists and clinicians, emphasizing early sharing of robust preclinical data. Ultimately, the goal of these partnerships is to proactively align priorities for expedited efficacy testing of the most promising agents in a diverse and representative panel of RMS models, including PK and PD studies, and to develop a platform for pre-trial biomarker discovery (Table 1).

Table 1:

Action Items for Future RMS Trial Development

Discipline	Action Item
Preclinical Testing (PIVOT, PROXC)	• Align and expedite preclinical testing of promising agents • Enhance PK/PD testing • Prioritize agents for further study
DVL	• Identify planned trials where RMS-specific cohorts are indicated • Maximize RMS inclusion on disease-agnostic trials • Develop RMS-specific early-phase trials
Biostatistics	• Incorporate innovative trial designs to enhance trial efficiency • Conduct subset analyses to determine differential responses between RMS histologies
Pathology, Biology	• Standardize longitudinal tissue/blood collections • Design CRFs to integrate locally collected molecular data • Improve specimen submissions at relapse/progression • Design and execute translational studies using collected tissue/blood to identify novel targets and biomarkers
Radiology	• Refine the diagnosis/definition of in-transit nodes/regional lymph nodes and metastatic disease • Define the optimal imaging modalities and timepoints in treatment response assessment and relapse monitoring
Local Control	• Embed local control questions into trials (e.g., pre-operative XRT, reduction of XRT in subsets of patients, metastatic site XRT, DPE, sentinel lymph node sampling)
Mathematical Oncology	• Incorporate modelling dynamics of disease response and/or recurrence
Adolescent and Young Adult Oncology	• Enhance enrollment of AYA patients by collaborating with adult consortia
Cancer Control and Supportive Care	• Incoporate PROs and link them to primary study aims • Evaluate the burdens of toxicity • Include hypothesis-driven PK, PGx, and toxicity questions with targeted sample collection • Integrate collection of socio-economic determinants of health data
Survivorship	• Embed reminders for LTFU engagement into protocol roadmaps • Use LTFU data to ask retrospective questions from prior studies
Patient Engagement	• Meaningful equity-centered patient engagement from trial conception to completion • Engage underrepresented populations in current RMS studies to identify the barriers to accrual • Ensure that the outcomes most relevant to patients are incorporated into the trial
International Partnerships	• Collaborate on clinical studies of rare RMS subsets

Abbreviations: AYA: adolescent and young adult, CRF: case report form, DPE: delayed primary excision, DVL: developmental therapeutics, LFTU: long-term follow up, PGx: pharmacogenomic, PIVOT: Pediatric Preclinical in Vivo Testing, PK: pharmacokinetic, PROs: patient-reported outcomes, , PROXC: Pediatric Research Oncology Xenografting Consortium, RMS: rhabdomyosarcoma, XRT: radiotherapy

2). Improving efficiency of trial development and implementation through new partnerships

A second major challenge to advancing studies for RMS is the significant lag time between the identification of a preclinically active agent and entry into a phase 3 trial. Often this delay stems from a lack of essential early phase clinical data. In addition to the lack of preclinical data discussed above, our Task Force identified inadequate early phase clinical data as an impediment to immediate translation in three of five prioritized agents.¹⁵ Missing data included recommended pediatric phase 2 doses (RP2D), early activity signals, and feasibility data for incorporating these agents into therapeutic combinations. Since the publication of the Task Force’s report in 2021, some of the prioritized agents or agents in the same class have progressed into small early phase studies for patients with RMS. The status of these studies is detailed in Table 2 and includes those testing the poly-ADP-ribose polymerase (PARP) inhibitor olaparib, the histone deacetylase (HDAC) inhibitors entinostat¹⁹ and mocetinostat, the IGF-1R antibody ganitumab,²⁰ and two novel cytotoxic agents, PLX038 and eribulin.

Table 2:

Current status of select agents in categories prioritized by the 2020 COG RMS New Agents Task Force

Class	Agent	Trial	ID	Study Population	Current Status
PARP inhibitor	Olaparib	Phase 1, combined with temozolomide	NCT01858168	≥16 yo RMS, EWS	Active
HDAC inhibitor	Entinostat	Phase I	NCT02780804	≥1–21 yo solid tumors	Completed RP2D: 4 mg/m2 weekly Under consideration for future COG study
	Mocetinostat	Phase 1, combined with vinorelbine	NCT04299113	≥13 yo RMS only	Active
IGF-1R targeting	Ganitumab	Phase 1/2, combined with dasatinib	NCT03041701	≥2 yo RMS only	Phase 1 completed Phase 2 discontinued due to withdrawal of industry support
Novel cytotoxic	PLX038	Phase 1	NCT02646852	≥18 yo solid tumors	Completed, no results published yet
		Phase 1/2, combined with rucaparib	NCT04209595	≥18 yo solid tumors	Phase 2 discontinued due to withdrawal of industry support
	Eribulin	Phase 2	NCT03441360	≥1–18 yo RMS, NRSTS, EWS	Completed RMS Cohort: median PFS 1.7 months; median OS 5.1 months

Abbreviations: COG: Children’s Oncology Group, EWS: Ewing sarcoma, HDAC: histone deacetylase, ID: Clinicaltrials.gov identification number, IGF-1R: insulin-like growth factor receptor type 1, NRSTS: non-rhabdomyosarcoma soft-tissue sarcoma, OS: overall survival, PARP: poly-ADP ribose polymerase, PFS: progression-free survival, RMS: rhabdomyosarcoma, RP2D: recommended phase 2 dose, yo: years old

Based on these newly available clinical data, it is evident that most prioritized agents are still not ready for phase 3 clinical trials. Furthermore, the current paradigm for identifying active agents for RMS, progressing them through early phase clinical trials, and implementing phase 3 studies is a prohibitively lengthy process. For instance, 22 years elapsed from the first publication demonstrating the preclinical activity of mTOR inhibition in RMS to the initiation of a phase 3 trial testing temsirolimus in combination with chemotherapy in newly diagnosed patients with RMS (ARST1431).²¹ Since a key goal of the RMS Clinical Trials Strategy Task Force is to improve the efficiency of initiating and implementing RMS clinical trials, we will need to further enhance collaboration through new partnerships.

To address some of these barriers, our Task Force has engaged with the COG Developmental Therapeutics (DVL) committee, a group with substantial experience in conducting early phase trials and a proven ability to execute trials on a short timeline from concept development to trial initiation. Studies conducted through the DVL committee can be opened at many COG institutions and have the advantage of more rapid accrual than single or limited-site studies.²² In addition, the close collaboration between the DVL committee and industry partners may help to ensure drug access throughout the clinical development process.

To facilitate a more formalized engagement between the STS and DVL committees and capitalize on the respective expertise of each group, we have established ongoing collaborative meetings. The primary objectives of these meetings are threefold: (1) to review agents in the DVL early clinical development pipeline to determine whether any are appropriate for RMS-specific expansion cohorts following dose-finding, (2) to ensure the inclusion of RMS patients in DVL trials with disease-agnostic, biomarker-driven cohorts, and (3) to develop, when appropriate, early-phase RMS-specific trials within the NCI-supported PEP-CTN (Pediatric Early Phase Clinical Trials Network), following the precedent of other COG disease committees, such as acute myeloid leukemia (NCT04203316) and osteosarcoma (NCT04616560). Established dose determination and preliminary efficacy data generated from these early phase trials can lay the groundwork for developing future STS committee studies. Additionally, where suitable, we suggest implementing innovative clinical trial designs, such as “seamless” designs, to consolidate trial phases, expedite the acquisition of efficacy markers, enhance patient access to novel agents, and facilitate earlier drug approval if safety and efficacy are demonstrated.^23,24 In concert with the preclinical pipeline effort, this partnership may facilitate trial development before full publication of preclinical data, substantially shortening current timelines (Table 1). Ultimately, harmonizing shared data amongst these preclinical and early phase clinical groups will be a powerful resource that can accelerate advancements in RMS treatment.

Finally, for rare subsets of RMS, such as those with MYOD1 mutations, where rapid trial accrual is challenging, we propose global collaborations to facilitate sufficient participant accrual within a reasonable time. This strategy has been effective for studying new agents in other rare pediatric cancer populations, such as blinatumomab for relapsed or refractory B-acute lymphoblastic leukemia in AALL1121/MT103–205, front-line treatment for hepatoblastoma in AHEP0731 and AHEP1531, and front-line treatment for germ cell tumors in AGCT1531 and AGCT1532.^25–30 The recent establishment of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) has created a robust foundation for these endeavors for RMS.³¹ In addition, collaborative trials with adult consortia may aid these recruitment efforts. For more common RMS subtypes, such as those with PAX3::FOXO1 or PAX7::FOXO1 fusions, we recommend that future trials prioritize the inclusion of secondary and/or exploratory aims to evaluate differential responses within RMS subgroups to enable a deeper understanding of their clinical behavior, aiding in the development of tailored treatment approaches going forward (Table 1).

3). Expanding opportunities for knowledge generation during the conduct of clinical trials

Phase 3 clinical trials are crucial for advancing treatment options for newly diagnosed childhood cancers, including RMS. However, these trials often prioritize the evaluation of novel agents or approaches compared to the standard of care, leaving many other important questions about the biology, outcomes, and care of patients unanswered, with few opportunities to conduct separate trials to address them. Our ability to improve the care of patients with RMS requires going well beyond the introduction of novel agents, and optimal treatment necessitates contributions from multiple disciplines. Despite this, our clinical trials have historically only addressed such topics as exploratory objectives or post-hoc analyses. We believe a more systematic and comprehensive approach to RMS trial development, including early engagement of a diverse group of vital stakeholders at the concept development stage, will maximize the quantity and quality of knowledge generated from each study. This, in turn, will offer opportunities to capture valuable data, even in studies where primary objectives are not met, thereby advancing RMS care and outcomes more comprehensively. This approach will maximize the use of resources and participant involvement. Thus, we propose the engagement of multidisciplinary experts early in concept development to allow for the incorporation of potential study aims within their areas of expertise for each upcoming study. This includes basic and translational scientists, pathologists, radiologists, radiation oncologists, surgeons, clinical pharmacologists, oncologists with expertise in health disparities research, oncologists with expertise in treating young adults, and patient advocates. By incorporating their expertise into concept development, we can broaden the aims of future studies to improve outcomes for patients with RMS regardless of the success of new drugs. This will involve collection of diverse data types, including uniformly collected, clinically annotated tissue and blood samples for multi-omics analyses (e.g., pharmacogenomics (PGx), proteomics, transcriptomics, metabolomics), radiological outcomes, and drug doses received compared to protocol-specified doses to better reflect actual treatment received, concurrent medications with chemotherapy that may affect treatment response, details of surgical and radiation approaches, patient-centered outcomes, and social determinants of health (SDOH) (Table 1).

Emerging questions in RMS biology and pathology include tumor evolution from diagnosis to relapse, the potential role of AI/machine learning (ML) in diagnosis and prognostication, and the role of blood-based disease markers in prognosis and therapeutic decision-making. Considering these questions during the design of clinical trials provides an opportunity not only to acquire highly annotated biological specimens linked with clinical data on uniformly treated patients, but also to use these specimens to answer important questions about RMS biology. With an evolving understanding of the molecular landscape of RMS, molecular features will also play an increasingly vital role in risk stratification and treatment selection at diagnosis. The Molecular Characterization Initiative (MCI) will aid in these efforts by facilitating robust, uniform, and clinically annotated genomic tumor and germline characterization for patients enrolling on COG RMS trials.^32,33 MCI-generated de-identified molecular and clinical data will also be available for investigator requests, providing a tool for improved understanding of the underlying biology of RMS. Indeed, the currently accruing low-risk study ARST2032 (NCT05304585) requires co-enrollment on the MCI, which provides FOXO1 fusion status and MYOD1 and TP53 mutation status and informs treatment assignment on the trial.^34,35 Uniformity in both sample acquisition and analysis, both centrally and institutionally, must also be emphasized and, where possible, standardized within protocols.^36,37 As relapsed disease remains less understood than primary disease, prioritizing efforts to obtain tumor tissue at the time of relapse will provide a valuable resource for studying tumor evolution and treatment resistance. Emerging technologies, including AI/ML tools to diagnose subtypes of RMS and generate predictive models based on pathology slides,^38–40 and blood-based disease detection methods, including circulating tumor DNA (ctDNA), to provide prognostic information at diagnosis and while on-therapy,^35,41–44 represent areas of exploration that should be incorporated into future trials. Initial feasibility aims could support subsequent aims investigating their prognostic and potentially therapeutic value.

The optimal radiologic strategy for disease staging, response assessment, and short- and long-term surveillance in RMS remains uncertain, presenting a critical area for refinement in future COG RMS trials. Patterns of regional and metastatic spread in RMS are distinct from bone sarcoma and other soft tissue sarcomas; radiologic assessments of RMS must continue to evolve to improve the accuracy of staging and surveillance.^45,46 Recent and ongoing COG RMS trials have included objectives investigating the relationship between early fluorodeoxyglucose positron emission tomography (FDG-PET) response and survival, an enduring question due to a substantial body of conflicting literature on the utility of early disease response in predicting outcome.^47–53 Other outstanding questions for future studies include how to refine the radiologic definitions of local invasion, regional, and metastatic disease, integrate FDG-PET into disease-response assessments, and select optimal time points for disease imaging during and after treatment. As we improve our understanding of cancer as a dynamic evolutionary process affected by selection pressure (i.e., systemic and local therapy), we can use mathematical modeling to quantify rates of disease growth, therapy response, and drug resistance. Longitudinal imaging studies may be leveraged for data (potentially integrated with longitudinal blood-based disease detection and sequencing) to calibrate such models and generate virtual patient cohorts. These cohorts can be used to explore novel strategies for treatment timing, agent selection and sequencing, and dynamic decision support. In addition, this approach can aid in identifying optimal timing for radiologic assessment and biomarker collection, to maximize the prognostic information gathered during therapy.^54,55

Recent advances in local control strategies for RMS have included studying delayed primary excision (DPE) for select patients, establishing standardized regional staging procedures, optimizing radiation dose based on IRS group, fusion status, initial tumor size, early disease response, and incorporating radiation guidelines around DPE.⁵⁶ Despite this, questions persist regarding the optimal therapy for local control, including determining the most effective local control strategy based on anatomic site and other clinical factors, defining the interplay between local control rates and chemotherapy dosing, and addressing metastatic site control challenges.^57,58

The prevalence of racial and/or ethnic health disparities and the impact of SDOH on outcomes for patients with RMS are largely unknown. A retrospective analysis of COG study participants demonstrated that self-identified Black and Hispanic patients with RMS were more likely to present with high-risk features but did not experience differences in event-free or overall survival when treated on clinical trials.⁵⁹ However, the influence of SDOH on RMS outcomes has not been analyzed. In other childhood cancers, poverty and insurance type are known risk factors for inferior survival in the clinical trial setting, highlighting the importance of systematically evaluating SDOH as potential risk factors for inferior disease outcomes.^60,61 Recent efforts have demonstrated that trial-embedded collection of SDOH data on COG trials is feasible.⁶² Given its geographic reach across North America, COG represents an essential mechanism to facilitate (1) evaluation of the external validity of trial data including generalizability of toxicity endpoints and functional and disease outcomes across the population of children with cancer; (2) evaluation of the internal validity of trial data given that SDOH are independently associated with trial survival outcomes in other diseases and thus failure to incorporate SDOH in trial analyses may result in bias akin to failure to collect known biological prognosticators; (3) identification of populations of children for whom future social support interventions may be warranted to improve outcomes. In RMS, where even baseline data on SDOH are lacking, we propose prospective collection of SDOH data to determine if social and environmental factors at diagnosis are outcome predictors.

Finally, as a substantial portion of RMS cases occurs in adolescents and young adults (AYA), certain aspects of therapy may need to be refined to maximize the cure rate and quality of life in this age group.⁶³ Collaborative engagement during trial development between COG and other national cooperative groups representing AYA patients could be mutually beneficial, facilitating the inclusion of AYA patients who may not typically be offered enrollment on COG studies. This would improve the representation of AYA patients on these studies while standardizing treatment across the populations.

4). Addressing toxicity and quality of life through integration of patient-reported outcomes

The treatment of RMS leads to significant short- and long-term adverse effects (AEs) in children, affecting multiple aspects of their physical, psychological, and social health.^64–67 However, there is an incomplete understanding of the underlying causes of AE distribution and intensity, particularly as reported by patients themselves. For instance, analysis of clinician-reported AEs from IRS-IV study demonstrated that adolescents undergoing treatment for RMS experience more peripheral neuropathy and less myelosuppression than younger children.⁶⁵ Additionally, adolescents with metastatic RMS also reported more nausea and vomiting, were more prone to unplanned dose interruptions, and had lower treatment completion rates than younger patients.⁶⁶ While age is recognized as an independent prognostic factor in RMS, it remains unclear whether the higher rate of observed toxicities among adolescents is related to an enhanced ability of adolescents to communicate their symptoms due to developmental maturity than younger children, or is a reflection of varied pharmacokinetics or genetic susceptibility.^68,69 Relatedly, lower rates of myelosuppression observed in adolescents compared to younger children with RMS might reflect inadequate alkylator dosing for this age group. To minimize toxicity, optimize therapeutic outcomes, and provide age-appropriate supportive care for patients across different age groups, gaining a more comprehensive understanding of the potential factors underlying the variability of these adverse effects is crucial. To systematically address these questions, we suggest incorporating data on PK/PD, PGx, patient-reported outcomes (PRO) on- and off-treatment, and long-term follow-up as applicable into future RMS trials (Table 1).

An understanding of both PGx and PK/PD is crucial for optimizing therapeutic outcomes. By incorporating PGx assessments into future RMS clinical trials, as appropriate, we can begin to explore how genetic variations influence drug responses. This approach, which has successfully been used in other oncologic populations,^70,71 can illuminate the variability in adverse effects observed among different subsets of a study population, identify the genetic factors and mechanisms contributing to differences in drug response and toxicity, and aid in developing strategies to minimize treatment-related complications.^72,73 Similarly, a comprehensive understanding of the factors influencing PK and PD of drugs utilized for RMS treatment is crucial to minimize toxicity and enhance treatment efficacy across diverse patient populations such as infants, adolescents, or patients with high BMI.^74–76

Our current understanding of the toxicity associated with RMS treatment primarily relies on clinician-reported AEs. Studies have shown a discordance between clinician or caregiver-reported symptoms and children’s self-report.⁷⁷ In adults with cancer, collection of PROs is associated with improved accuracy of identification of AEs during cancer treatment, quality of life, and overall survival.^78–80 The availability of validated and reliable PRO tools such as Pediatric PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) and Patient-Reported Outcomes Measurement Information System (PROMIS) to assess symptomatic AEs and function in children as young as seven years by self-report provides a unique opportunity to include the study participant’s perspective in measuring the impact of RMS therapy.^77,81 In interventional clinical trials, understanding treatment tolerability from the participant’s perspective is a central element for assessing the toxicities of novel agents and is critical to maximizing quality of life. The incorporation of pediatric PROs in drug development has also been prioritized by the US Food and Drug Administration’s (FDA) Patient-Focused Drug Development (PFDD) initiative.⁸² Therefore, it is indispensable that future RMS trials incorporate longitudinal PRO measures to provide valuable insights into the lasting effects of RMS therapy on patients’ physical, psychological and social well-being and to tailor supportive care interventions accordingly.^83–85

A substantial knowledge gap also exists regarding the long-term health of childhood survivors of RMS. While most children with RMS will survive their cancer, they may endure long-term treatment-related effects on their physical, mental, sexual, and reproductive health. Thus, future trials must continue to explore how changes in various treatment approaches, such as dosing of chemotherapy and radiation or type of surgery, influence the long-term outcomes.^86–88 Close collaborations with the COG survivorship committee and developing an infrastructure to support these efforts are vital to accomplishing these objectives and will enable trial participants to be engaged early in long-term follow-up studies. Besides providing critical information necessary for comprehensive care for RMS survivors, robust collection of long-term data, including PRO data, can also better inform the balance between treatment efficacy and long-term toxicity for future RMS therapies.

5). Prioritizing patient engagement

Patient engagement has increasingly been acknowledged by national and international research organizations as crucial to the research process, with some oncology cooperative groups developing frameworks for authentic patient involvement in clinical trial conduct.^{89,90 91} Integrating the values and perspectives of patients and/or their caregivers is essential to ensure a patient-centered approach throughout research development. Their involvement includes but is not limited to prioritizing relevant questions for clinical trials, contributing to trial design and development, assessing the feasibility of the study from the patient perspective, identifying potential barriers and enablers of patient accrual, improving effective communication with patients, capturing of relevant data, supporting the interpretation and dissemination of trial findings, and developing strategies for future trials.^91,92 Importantly, this engagement should not be tokenistic; it must be meaningful, equity-centered, and adhere to evidence-based methodologies and frameworks established by agencies such as the Patient-Centered Outcomes Research Institute, recognizing patients as key stakeholders.⁹³ Therefore, to develop clinical trials that better address the needs and preferences of those affected by RMS, future RMS trials should meaningfully and consistently engage patients and/or their caregivers to foster patient-centeredness in each aspect of the research process.

CONCLUSION

Despite the numerous challenges associated with the development and implementation of phase 3 clinical trials for children, adolescents, and young adults with RMS, these studies remain paramount for advancing our understanding and improving outcomes for patients with RMS. We have presented a strategic framework (Table 1) to enhance the development and conduct of future trials, centered around including multiple stakeholders, all of whom share a common vision of improving outcomes for patients with RMS.

Abbreviations Table

AE

Adverse Effect

AI/ML

Artificial Intelligence/Machine Learning

AYA

Adolescent and Young Adult

COG

Children’s Oncology Group

ctDNA

Circulating Tumor DNA

DPE

Delayed Primary Excision

DVL

Developmental Therapeutics

FDA

Food and Drug Administration

FDG-PET

Fluorodeoxyglucose Positron Emission Tomography

HDAC

Histone Deacetylase

INSTRuCT

INternational Soft Tissue SaRcoma ConsorTium

IRSG

Intergroup Rhabdomyosarcoma Study Group

MCI

Molecular Characterization Initiative

NCI

National Cancer Institute

PARP

poly-ADP-ribose polymerase

PD

Pharmacodynamics

PDX

Patient-derived Xenograft

PEP-CTN

Pediatric Early Phase Clinical Trials Network

PFDD

Patient-focused Drug Development Initiative

PGx

Pharmacogenomics

PIVOT

Pediatric Preclinical in Vivo Testing

PK

Pharmacokinetics

PPTC

Pediatric Preclinical Testing Consortium

PPTP

Pediatric Preclinical Testing Program

PRO

Patient-reported Outcomes

PRO-CTCAE

Patient-reported Outcomes Common Terminology Criteria for Adverse Events

PROMIS

Patient-reported Outcomes Measurement Information System

PROXC

Pediatric Research Oncology Xenografting Consortium

RMS

rhabdomyosarcoma

SDOH

Social Determinants of Health

STS

soft tissue sarcoma