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Background: Children with relapsed CNS tumors, neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. Here we describe a study to determine the feasibility of leveraging genomic profiling results within a molecular tumor board (MTB) to make real-time treatment decisions for children with relapsed/refractory solid tumors. Methods: Subjects were divided to 3 strata: Strata 1: Relapsed/refractory neuroblastoma, Strata 2: Relapsed/refractory CNS tumors, and Strata 3: Relapsed/refractory rare solid tumors. Samples were sent for tumor/normal whole exome (WES) and tumor whole transcriptome sequencing, and the genomic data were used in a 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 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of CR, PR, SD, NED, and PD subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. Results: 144 eligible subjects were enrolled with 144 evaluable for safety and 124 evaluable for response. Tumor types included neuroblastoma (n=31), CNS tumors (n=41), and rare tumors (n=72). Sarcomas (n=40) were the most common tumor type in the rare tumor stratum. The average time from biopsy to completion of DNA/RNA sequencing was 10 days (range 2-31 days); to completed analysis and drug prediction report, 17 days (8-41); 23 days (10-66) to MTB decisions; and 38 days (18-146) to initiation of the 4-drug combination agreed upon by the MTB. Treatments were selected on DNA and RNA findings in 19.5% of cases and in 80.5% on RNA alone. Patient benefit was exhibited in 70% of all subjects, 85% of neuroblastoma subjects, 73% of CNS tumor subjects, and 62% of rare tumor subjects. AEs occurred in Conclusions: It has been well-established that comprehensive genomic sequencing is the future of precision medicine. Here, we have demonstrated the feasibility, efficacy, and safety of a comprehensive sequencing model to guide targeted therapy for patients with any relapsed/refractory solid malignancies. Targeted therapy was well tolerated, and the response benefit rate of 70% in these heavily pretreated populations suggests that this treatment could be an effective option for relapsed and refractory pediatric cancers. Citation Format: Giselle L. Saulner Sholler, Jacqueline Kraveka, Genevieve Bergendahl, Elizabeth Lewis, William Ferguson, Abhinav Nagulapally, Karl Dykema, Valerie Brown, Michael Isakoff, Joseph Junewick, Deanna Mitchell, Don Eslin, Virginia Harrod, William Roberts, Javier Oesterheld, Randy Wada, Jawhar Rawwas, Devang Pastakia, Kevin Ginn, Raya Saab, Kevin Bielamowicz, Jason Glover, Eugenia Chang, Gina Hanna, Daniel Enriquez, Tyler Izatt, Rebecca Halperin, Sara Byron, William Hendricks, Jeffrey Trent. Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT089.

10010 Background: Long term survival in HRNB patients remains a challenge with relapse as the primary cause of mortality. DFMO has been evaluated as a chemopreventative therapy in a single arm study designed to compare EFS outcomes with published rates for the Phase 3 Children’s Oncology Group ch14.18 immunotherapy trial, ANBL0032. In order to address the limitations associated with comparison to a historical control group, we used ANBL0032 patient-level data and propensity-score matching (PSM) to simulate a randomized study comparing EFS of patients treated with DFMO after ch14.18 (treated) to ANBL0032 patients who did not subsequently receive DFMO (control). Methods: A phase 2 trial enrolled a total of 140 HRNB patients in remission at the completion of disease treatment from 2012 to 2016. Patients received 2 years of continuous treatment with DFMO 750 ±250 mg/m2 BID and were followed for up to 7 years. ANBL0032 enrolled a total of 1328 HRNB patients from 2001 to 2015 who were assigned to treatment with ch14.18 immunotherapy and followed for up to 10 years. With FDA input, we defined selection rules to identify like groups of treated and control patients eligible for matching, covariates of potential prognostic importance, and matching algorithm details. PSM was used to balance cohorts on their baseline demographic and characteristics, matching each treated patient with the 3 most closely scored control patients with an exact match on MYCN. The Kaplan-Meier method and Cox regression analyses were used to compare EFS (primary) and overall survival (OS) (key secondary) endpoints. Multiple sensitivity analyses were performed to further investigate the primary comparison. Results: A total of 92 treated patients and 852 control patients met selection criteria, with 91 and 516, respectively, having complete covariate data required for the analysis. Eighty-seven (94.6%) of the treated group had verified participation in ANBL0032 immediately prior to enrollment in the DFMO trial. EFS from end of immunotherapy was significantly improved in the matched DFMO group (n=90) vs. control group (n=270), with a hazard ratio of 0.48 (95% CI: 0.27, 0.85) and a p-value of 0.0114. Four-year EFS was 84.4% (95% CI 75.2, 90.5) in the DFMO group versus 72.8% (95% CI 67.0, 77.7) in the control group. OS rates were also higher for DFMO group in the matched population, with a hazard ratio of 0.36 (95% CI: 0.16, 0.79) and a p-value of 0.0105. EFS sensitivity analyses demonstrated consistent results, including those challenging selection criteria for the control population. Conclusions: Patients in remission after standard upfront therapy treated with DFMO had approximately half the risk of relapse compared to matched control patients. The PSM comparisons represent the most statistically robust findings to date supporting the benefit of DFMO as a maintenance treatment for HRNB. Clinical trial information: NCT02395666, NCT00026312.

10042 Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. A retrospective study of 35 such patients has reported an objective response rate of 17% and 4-month progression-free survival (PFS) of 56% with this combination (BMC Cancer 2016;16:280). Nab-paclitaxel is a nanoparticle taxane that has activity against osteosarcoma xenografts and may have less myelosuppression than docetaxel. The combination of gemcitabine and nab-paclitaxel is now frontline therapy for pancreatic cancer. We conducted a prospective multi-institutional phase II trial of this drug combination for patients with recurrent osteosarcoma. Methods: Patients with relapsed/refractory osteosarcoma with measurable disease and age ≥ 12 years and adequate organ function were included. A Simon’s two-stage design was used to identify a 4-month progression-free survival (PFS) of > 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 weekly x 3 in 4-week cycles. Results: Eighteen patients with a median age 16 years (range 12- 26) received a total of 56 total cycles.(median 2, range 1 - 12). The median number of prior treatment regimens was 3 (range 1-7). Two patients (11%) experienced a partial response, and 6 (33%) received more than 2 cycles. The 4-month PFS was 30% (95% CI 14-62 %). Six patients required dose reductions for neutropenia (n = 4), pleural effusion (1), or neuropathy (1). Two patients were removed from study secondary to neutropenia despite dose reduction and myeloid growth factor support, and one patient came off study due to severe peripheral edema. Conclusions: In this prospective study, the combination of gemcitabine and nab-paclitaxel administered on this schedule showed only limited activity for patients with heavily pretreated recurrent osteosarcoma. Toxicity led to dose modifications in 33% and discontinuation in 17% of patients. When compared to a historical retrospective study, the substitution of nab-paclitaxel for docetaxel did not appear to increase activity or decrease toxicity for this patient population. Clinical trial information: NCT02945800.

Background: TB-403 is a monoclonal antibody directed against placental growth factor (PlGF). In medulloblastoma (MB), PlGF promotes tumor progression by activating downstream pathways that promote cell proliferation, cell survival and metastasis. Elevation in PlGF expression, or its receptor neuropilin 1 (Nrp1), is found in tumor samples in a variety of small round blue cell tumors, including MB, neuroblastoma (NB), Ewing sarcoma (ES), and alveolar rhabdomyosarcoma (ARMS). Additionally, pre-clinical studies have shown that TB-403 inhibits primary tumor growth and spinal metastasis in mice with orthotopic MB grafts, and that mice treated with TB-403 survive significantly longer than untreated animals. PlGF is expressed across human MB subtypes, and high expression of the PlGF receptor Nrp1 correlates with poor overall survival. Objective: Evaluate the safety and maximum tolerated dose (MTD) of TB-403 administered as a single agent during cycle 1 of therapy in children with relapsed or refractory MB, NB, ES or ARMS and measure pharmacokinetics (PK). Methods: A phase 1, open-label, multicenter, dose escalation study of TB-403 in pediatric subjects with relapsed or refractory MB, NB, ES or ARMS. The study involved 4 dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3+3 dose escalation scheme. A treatment cycle was 28 days. Subjects received 2 doses of TB-403 (on Days 1 and 15) per cycle unless they experienced toxicity. After cycle 1, temozolomide or etoposide could be added at the investigator's discretion. The primary objective was to determine the MTD of TB-403 monotherapy during a dose-limiting toxicity (DLT) assessment period or 1 cycle. The secondary and exploratory objectives included PK and plasma biomarkers respectively of TB-403 administered as a single agent or in combination with chemotherapy. For subjects who continued TB-403 treatment after the DLT assessment period, we evaluated preliminary efficacy. Results: Fifteen subjects enrolled; 3 to DL1 (Dose Level 1), 3 to DL2, 6 to DL3 and 3 to DL4. All subjects received 2 doses of TB-403 in cycle 1. Five serious treatment emergent adverse events were reported in 3 patients. None of these were considered serious unexpected adverse drug reactions. Conclusion: TB-403 was shown to be safe at all dose levels evaluated without reaching a MTD in pediatric subjects. Initial results look encouraging for incurable relapsed disease. Citation Format: Giselle L. Saulnier Sholler, Dan G. Duda, Genevieve Bergendahl, David Ebb, Matija Snuderl, Theodore W. Laetsch, Jennifer Michlitsch, Derek Hanson, Michael Isakoff, Kevin Bielamowicz, Jacquline Kraveka, Peter Carmeliet, Andy De Deene, Rakesh K. Jain. A phase 1 dose escalation study of TB-403 in pediatric relapsed or refractory medulloblastoma, neuroblastoma, Ewing sarcoma, or alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT015.

Abstract 866 Background: Dramatic improvements have been made in treating children with newly diagnosed acute lymphoblastic leukemia (ALL). However, poor outcomes are still observed in patients who are either refractory to or who have relapsed after conventional chemotherapy. Salvage therapy options are urgently needed for this patient population. Clofarabine is approved as a single agent for treatment of pediatric ALL in second relapse. Previously we reported the safety profile and response rates from the phase 1 study assessing clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory/relapsed acute leukemia (Hijiya, Leukemia, 2009). Here we report the phase 2 results. Methods: Patients (pts) aged 1–21 years with refractory/relapsed ALL were treated at the recommended phase 2 dose of clofarabine 40 mg/m2/day, cyclophosphamide 440 mg/m2/day, and etoposide 100 mg/m2/day. All 3 agents were given IV daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients could receive up to 2 induction cycles, followed by consolidation (max 8 cycles including induction). The primary endpoint was overall remission rate (ORR: complete remission [CR] and CR without platelet recovery [CRp]). Secondary endpoints were safety and tolerability, rate of partial remission (PR), duration of remission (DOR), event-free survival (EFS), 4-month EFS, and overall survival (OS). Minimal residual disease (MRD) by flow cytometry was evaluated as an exploratory endpoint. Results: Phase 2 comprised 25 pts (median follow-up 10.7 weeks [wks]): 16 males and 9 females with a median age of 14.0 years. Twenty-one pts had pre-B cell ALL, 1 pt had T cell ALL and 3 pts had an unknown immunophenotype. Fourteen pts had 2 prior induction regimens, 7 pts had 3 prior induction regimens and 4 pts had 1 prior induction regimen. Fifteen pts (60%) were refractory to their immediately preceding regimen. Four pts had received a prior hematopoietic stem cell transplant (HSCT). The investigator-assessed ORR was 44%; 7 CR (28%) and 4 CRp (16%). Additionally, 3 pts (12%) achieved PR. Eight pts were evaluable for MRD after induction, 5 were MRD negative (defined as Conclusions: Combination treatment with clofarabine, etoposide and cyclophosphamide in pediatric pts with refractory or relapsed ALL resulted in an ORR of 44% and negative MRD in heavily treated pts. Ten pts including 7 of 11 responders proceeded to HSCT. The safety profile is acceptable in this relapsed/refractory population. Disclosures: Hijiya: Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of clofarabine in combination with etoposide and cyclophosphamide. Paul:Genzyme: Employment, Equity Ownership. Borowitz:genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Isakoff:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Silverman:Genzyme: Research Funding; Enzon : Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steinherz:Genzyme: Research Funding. Kadota:Genzyme: Employment, Equity Ownership. Pressey:Genzyme: Research Funding. Shen:Genzyme: Research Funding. Chu:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cooper:Genzyme: Research Funding. Jeha:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Razzouk:Genzyme: Research Funding. Rytting:Genzyme: Research Funding. Barry:Genzyme: Employment, Equity Ownership. Carroll:Genzyme: Research Funding. Gaynon:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.