van Noesel, Max M

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Received: 1 December 2022 Revised: 28 January 2023 Accepted: 30 January 2023DOI: 10.1002/pbc.30257 PediatricBlood &Cancer The American Society ofPediatric Hematology/OncologyH I GH L I GH TDowe needmore clinical trials?MaxM. vanNoesel1,21Department of Solid Tumors, PrincessMáxima Center for Pediatric Oncology, Utrecht, Netherlands2Division Imaging &Oncology, UniversityMedical Center Utrecht, Utrecht, NetherlandsCorrespondenceMaxM. vanNoesel, Department of Solid Tumors, PrincessMáxima Center, Heidelberglaan 25, 3584 CSUtrecht, Netherlands.Email: m.m.vannoesel@prinsesmaximacentrum.nlFor most pediatric oncologists, this is a rhetorical question. More isbetter!In recent decades, pediatric oncologists have gained access to novelcompounds and pharma companies. The field engaged in internationalorganizations such as SIOP, COG, ITCC, PNOC, NANT, and many oth-ers and defined important targets for clinical research. These extensiveefforts resulted in many early drug trials for (by default rare) pediatrictumors.In this issue, Nader et al.1 investigated the international achieve-ments for neuroblastoma trials in their study: Systematic review ofdrug development activities for neuroblastoma from 2011 to 2020. Theirapproach was straightforward: they evaluated therapeutic trials forpatients with neuroblastoma as registered on https://clinicaltrials.gov/, Clincaltrialregister.eu, PubMed, and American Society of ClinicalOncology (ASCO).In summary, they identified 192 studies thatmet the inclusion crite-ria, almost equally divided between phase 1 (45%) and phase 2 (51%)studies, and only five phase 3 studies (2.6%). Eighty-nine percent ofstudies (157) concerned with at least one novel agent and roughly halfwere combination studies, mostly with conventional chemotherapy. Intotal, 118 agents were aimed at 78 targets. From the phase 1/2 orphase 2 studies, only 44% were aimed at response as primary out-come measure. In total, eight agents were evaluated by FDA (Food &Drug Administration, USA) or EMA (European Medicine Agency, EU)and only one was registered and included in standard treatment (GD2antibodies).On one hand, these results should be embraced and seen as a vic-tory for all the efforts of the pediatric oncology community: on average,20 new clinical studies for neuroblastoma or basket studies includingneuroblastoma each year. Seven of nine top priority targets as definedby the ACCELERATE platform for innovations for children and ado-lescents with cancer (https://www.accelerate-platform.org) strategyThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and nomodifications or adaptations aremade.© 2023 The Authors. Pediatric Blood & Cancer published byWiley Periodicals LLC.were investigated.2 Anti-GD2 antibodies were the subject of 16.7% oftrials and ultimately approved by both FDA and EMA. These antibod-ies have increased the overall survival of neuroblastoma patients by16%, and unlocked a large field of new clinical studies based on GD2antibodies.3 The second target of interest, ALK, will most probablybecome important as well in the treatment of neuroblastoma patientswith ALK-altered tumors.At the same time, we should be critical on the achievements inthe field. From a patient and parent perspective, it is striking howmany patients were involved in these studies that led to only oneregistered compound included in standard treatment. Although theauthors could not indicate the number of patients involved, we canmake an educated guess: considering all the studies and assuming aminimum of roughly 30 patients for each phase 1 study and 70 forphase 2, an estimated total of 7500 patients participated in thesestudies. And even when we only count 44% of phase 2 studies withresponse as primary outcome measure, it still concerns with roughly2500 patients. Indeed, there is a very small chance that an individualpatient will benefit from a trial! How can we improve the effective-ness of trials for patients, and what are the developments in thefield?The basis is straightforward: patients must be included in strictlybiomarker-driven studies, and studies should better predict theexpected results based on research. This is mostly achieved by usingthe pipeline of precision medicine, including molecular analysis of thepatient’s tumor for presence of the biomarker of interest. The com-pound must have a positive track record in preclinical in vitro testingand in vivo models to test in animal models. The development, forinstance, of the ITCC-P4 consortium (https://www.itccp4.eu), a plat-form for patient-derived xenograft (PDX) mouse models for the majorpediatric tumors, is significant and can accelerate preclinical testing ofnovel compounds. However, the major problem is the ineffectivenessPediatr Blood Cancer. 2023;70:e30257. wileyonlinelibrary.com/journal/pbc 1 of 2https://doi.org/10.1002/pbc.302572 of 2 VANNOESELof compounds or combinations with novel compounds in positivelyselected patients based on their biomarker profile. Obviously, ourmodels are often not predictive for the in-patient tumor response.More predictive biomarkers are needed.An important development is the emergence of ex vivo compoundscreening of the patient’s tumor cells. It means that tumor samplesof the patient become exposed to a large panel of drugs or drugcombinations to evaluate the tumor response and select the mosteffective drug (combination). Several techniques are in development.The most established technique uses patient-derived organoids. Thisdevelopment had already opened the field of adult oncology someyears ago for compound screening and made it possible to predictthe response of the patient better, that is, in metastatic colorectalcancer.4 The disadvantage of organoid culture is that the time to estab-lish a stable organoid for compound screening often conflicts with theurgent need of the patient to start treatment on short notice. One canforesee that this will be a major drawback in fast-growing pediatrictumors.Two recent techniques may provide a better solution. First, thedevelopment of patient-derived micro-organospheres.5 In short, thistechnique captures tumor cells in a microfluidic droplets platformto generate micro-organospheres in a high-throughput fashion formultiple-drug anddrug-combination testing. Again, thiswas effectivelyshown to be feasible and predictive in metastatic colon cancer, buthas not yet been tested in pediatric cancer. The second techniqueis based on direct culture of patient-derived tumor cells.6 The basisof the technique and feasibility was already established for high-riskpediatric cancer patients.6 Although these different techniques arenot yet available for routine screening of patient-derived tumors, theyhave the potential to add a different dimension to the biomarker test-ing in patients. Together with precision medicine, this will not onlyimprove the selection of the highest ranking trial for an individualpatient, but the combined data can also feed back into improving ourunderstanding of the really valuable biomarkers for patients.So, in conclusion: yes, we need more clinical studies, but we have anobligation to better select our patients for the right trial and improveour prediction of the effectiveness of the compounds. Let us hope,these novel strategies will have a positive impact on the outcome ofcancer in children.CONFLICT OF INTEREST STATEMENTThe authors declare no conflicts of interest.LINKED ARTICLEThis article is linked to an article by Jaclynne H. Nader et al. https://onlinelibrary.wiley.com/doi/epdf/10.1002/pbc.30106ORCIDMaxM. vanNoesel https://orcid.org/0000-0003-0503-5838REFERENCES1. Nader JH, Bourgeois F, Bagatell R, et al. Systematic review of clini-cal drug development activities for neuroblastoma from 2011 to 2020.Pediatr Blood Cancer. 2022:e30106. doi:10.1002/pbc.301062. Moreno L, Pearson ADJ, Paoletti X, et al. Early phase clinical trials ofanticancer agents in children and adolescents - an ITCCperspective.NatRev Clin Oncol. 2017;14(8):497-507.3. YuAL,GilmanAL,OzkaynakMF, et al. Long-term follow-up of a phase IIIstudy of ch14.18 (dinutuximab) + cytokine immunotherapy in childrenwith high-risk neuroblastoma: COG study ANBL0032. Clin Cancer Res.2021;27(8):2179-2189.4. Ooft SN, Weeber F, Dijkstra KK, et al. Patient-derived organoids canpredict response to chemotherapy in metastatic colorectal cancerpatients. Sci Transl Med. 2019;11(513):eaay2574.5. Ding S, Hsu C, Wang Z, et al. Patient-derived micro-organospheresenable clinical precision oncology. Cell Stem Cell. 2022;29(6):905-917.e6.6. Lau LMS,Mayoh C, Xie J, et al. In vitro and in vivo drug screens of tumorcells identify novel therapies for high-risk child cancer. EMBOMol Med.2022;14(4):e14608.How to cite this article: van NoeselMM. Dowe needmoreclinical trials? Pediatr Blood Cancer. 2023;70:e30257.https://doi.org/10.1002/pbc.30257 15455017, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pbc.30257 by Utrecht University Library, Wiley Online Library on [01/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Do we need more clinical trials?

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Do we need more clinical trials?

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