PMID- 38347552 OWN - NLM STAT- MEDLINE DCOM- 20240214 LR - 20240214 IS - 1756-994X (Electronic) IS - 1756-994X (Linking) VI - 16 IP - 1 DP - 2024 Feb 12 TI - Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial. PG - 28 LID - 10.1186/s13073-024-01297-5 [doi] LID - 28 AB - BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors. METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. RESULTS: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. CONCLUSIONS: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014. CI - (c) 2024. The Author(s). FAU - Sholler, Giselle L Saulnier AU - Sholler GLS AUID- ORCID: 0000-0002-5599-4757 AD - Division of Pediatric Hematology/Oncology, Penn State Health Children's Hospital, 500 University Drive, MC-H085, Rm. C7621, Hershey, PA, 17033-0850, USA. gsaulniersholler@pennstatehealth.psu.edu. FAU - Bergendahl, Genevieve AU - Bergendahl G AD - Division of Pediatric Hematology/Oncology, Penn State Health Children's Hospital, 500 University Drive, MC-H085, Rm. C7621, Hershey, PA, 17033-0850, USA. FAU - Lewis, Elizabeth C AU - Lewis EC AD - Levine Children's Hospital, Atrium Health, Charlotte, NC, USA. FAU - Kraveka, Jacqueline AU - Kraveka J AD - Medical University of South Carolina, Charleston, SC, USA. FAU - Ferguson, William AU - Ferguson W AD - Cardinal Glennon Children's Medical Center, St. Louis University School of Medicine, St. Louis, MO, USA. FAU - Nagulapally, Abhinav B AU - Nagulapally AB AD - Division of Pediatric Hematology/Oncology, Penn State Health Children's Hospital, 500 University Drive, MC-H085, Rm. C7621, Hershey, PA, 17033-0850, USA. FAU - Dykema, Karl AU - Dykema K AD - Levine Children's Hospital, Atrium Health, Charlotte, NC, USA. FAU - Brown, Valerie I AU - Brown VI AD - Division of Pediatric Hematology/Oncology, Penn State Health Children's Hospital, 500 University Drive, MC-H085, Rm. C7621, Hershey, PA, 17033-0850, USA. FAU - Isakoff, Michael S AU - Isakoff MS AD - Connecticut Children's Medical Center, Hartford, CT, USA. FAU - Junewick, Joseph AU - Junewick J AD - Helen DeVos Children's Hospital, Spectrum Health, Grand Rapids, MI, USA. FAU - Mitchell, Deanna AU - Mitchell D AD - Helen DeVos Children's Hospital, Spectrum Health, Grand Rapids, MI, USA. FAU - Rawwas, Jawhar AU - Rawwas J AD - Children's Hospitals and Clinics of Minnesota, Minneapolis, USA. FAU - Roberts, William AU - Roberts W AD - Rady Children's Hospital-San Diego and UC San Diego School of Medicine, San Diego, CA, USA. FAU - Eslin, Don AU - Eslin D AD - St. Joseph's Children's Hospital, Tampa, FL, USA. FAU - Oesterheld, Javier AU - Oesterheld J AD - Levine Children's Hospital, Atrium Health, Charlotte, NC, USA. FAU - Wada, Randal K AU - Wada RK AD - Kapiolani Medical Center for Women and Children, University of Hawaii, Honolulu, HI, USA. FAU - Pastakia, Devang AU - Pastakia D AD - Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. FAU - Harrod, Virginia AU - Harrod V AD - Dell Children's Blood and Cancer Center, Ascension Dell Children's, Austin, TX, USA. FAU - Ginn, Kevin AU - Ginn K AD - Children's Mercy, Kansas City, MO, USA. FAU - Saab, Raya AU - Saab R AD - Stanford Medicine Children's Health, Palo Alto, CA, USA. FAU - Bielamowicz, Kevin AU - Bielamowicz K AD - Arkansas Children's Hospital, Little Rock, AR, USA. FAU - Glover, Jason AU - Glover J AD - Randall Children's Hospital, Portland, OR, USA. FAU - Chang, Eugenia AU - Chang E AD - St. Luke's Cancer Institute, Boise, ID, USA. FAU - Hanna, Gina K AU - Hanna GK AD - Orlando Health Cancer Institute, Orlando, FL, USA. FAU - Enriquez, Daniel AU - Enriquez D AD - Translational Genomics Research Institute, Phoenix, AZ, USA. FAU - Izatt, Tyler AU - Izatt T AD - Translational Genomics Research Institute, Phoenix, AZ, USA. FAU - Halperin, Rebecca F AU - Halperin RF AD - Translational Genomics Research Institute, Phoenix, AZ, USA. FAU - Moore, Abigail AU - Moore A AD - Division of Pediatric Hematology/Oncology, Penn State Health Children's Hospital, 500 University Drive, MC-H085, Rm. C7621, Hershey, PA, 17033-0850, USA. FAU - Byron, Sara A AU - Byron SA AD - Translational Genomics Research Institute, Phoenix, AZ, USA. FAU - Hendricks, William P D AU - Hendricks WPD AD - Translational Genomics Research Institute, Phoenix, AZ, USA. FAU - Trent, Jeffrey M AU - Trent JM AD - Translational Genomics Research Institute, Phoenix, AZ, USA. LA - eng SI - ClinicalTrials.gov/NCT02162732 PT - Clinical Trial PT - Journal Article DEP - 20240212 PL - England TA - Genome Med JT - Genome medicine JID - 101475844 SB - IM MH - Child MH - Humans MH - *Neuroblastoma/drug therapy/genetics MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Neoplasm Recurrence, Local/drug therapy/etiology PMC - PMC10860258 OTO - NOTNLM OT - CNS tumors OT - Genomic sequencing OT - Molecular-guided therapy OT - Neuroblastoma OT - Orphan diseases OT - Pediatric oncology OT - Rare tumors COIS- The authors declare that they have no competing interests. EDAT- 2024/02/13 00:42 MHDA- 2024/02/14 12:50 PMCR- 2024/02/12 CRDT- 2024/02/12 23:45 PHST- 2023/08/17 00:00 [received] PHST- 2024/01/24 00:00 [accepted] PHST- 2024/02/14 12:50 [medline] PHST- 2024/02/13 00:42 [pubmed] PHST- 2024/02/12 23:45 [entrez] PHST- 2024/02/12 00:00 [pmc-release] AID - 10.1186/s13073-024-01297-5 [pii] AID - 1297 [pii] AID - 10.1186/s13073-024-01297-5 [doi] PST - epublish SO - Genome Med. 2024 Feb 12;16(1):28. doi: 10.1186/s13073-024-01297-5.