Janeway, Katherine A.

PURPOSE The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

Abstract Background This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. Methods Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. Results Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. Conclusion There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).

Abstract Background The National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. Methods Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. Results Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. Conclusion Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. ClinicalTrials.gov Identifier NCT03233204. IRB approved: initial July 24, 2017.

10006 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm I evaluated palbociclib, a reversible, selective oral small molecule inhibitor of CDK 4 and 6 in tumors harboring specified genomic alterations in the cyclinD-cdk4/6-INK4a-Rb pathway: amplification of CDK4, CDK6, CCND1, CCND2, or CCND3. Positive Rb expression by IHC was required. Methods: Palbociclib was administered on days 1-21 at 75 mg/m2 once daily in 28-day cycles for up to 2 years, until disease progression, or intolerable toxicity. Response assessment occurred every 2-3 cycles. The primary endpoint was objective response (OR) rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty-three patients (median age 15 yrs; range 9-21) were enrolled between August 2018 and May 2022. Twenty patients received protocol therapy and were evaluable for response. Of treated patients, osteosarcoma was the most common diagnosis (9/20, 45%), with amplification of CCND3 detected in 6/9 patients, CDK4 in 2, and CDK6 in 1. Rhabdomyosarcoma was next most frequent (6/20, 30%), with all tumors harboring CDK4 amplifications. Other diagnoses were high grade glioma (n = 2), soft tissue sarcoma (n = 2), and neuroblastoma (NB) (n = 1). Additional genomic alterations were detected in 9/20 tumors, most frequently TP53 mutations (n = 4, including 2 patients with Li-Fraumeni syndrome). Palbociclib was generally well tolerated with hematologic toxicities being the most common treatment related events and no related grade 5 events. Neutropenia was the most common grade 3-4 adverse event (n = 10, 50%) followed by thrombocytopenia (n = 8, 40%), leukopenia (n = 7, 35%), and anemia (n = 5, 25%). Four patients came off study for toxicity (3 for prolonged thrombocytopenia (cycle 1 (x2) and cycle 2) and 1 for prolonged grade 4 neutropenia (cycle 3)). Non-hematologic toxicities were mild (grade 1-2). No ORs were seen. Two patients with tumors harboring CDK4 amplifications had stable disease (SD): one with NB had SD for 5 cycles and one with sarcoma had SD for 3 cycles but came off therapy for toxicity. Six-month PFS was 10% (95% CI: 1.7%-27.2%) and six-month overall survival was 65% (95% CI: 40.3%, 81.5%). Conclusions: The CDK4/6 inhibitor palbociclib at 75mg/m2 PO daily was well tolerated in this heavily-pretreated cohort. No objective responses were observed in these biomarker-selected patients with treatment-refractory solid tumors. Further evaluation of this agent in combination with chemotherapy in the pediatric population is ongoing. Clinical trial information: NCT03526250 .

11529 Background: To evaluate clinical characteristics and patterns of treatment failure in patients with localized Ewing sarcoma (ES) treated on AEWS1031 according to local control (LC) strategies, tumor size, and tumor site. Methods: AEWS1031 was a phase 3 randomized trial comparing two interval compressed chemotherapy regimens. Patients who completed LC on AEWS1031 were analyzed. LC was with surgery alone (S), definitive radiation therapy (RT), or surgery plus radiation (S+RT), and determined by the treating investigator. Local failure (LF) and distant failure (DF) were defined as recurrence at primary tumor site or distant site, respectively. Fine and Gray method was used to estimate cumulative incidence of LF and DF from time LC was completed. P-values were calculated using logrank or Gray’s test, as appropriate. A two-sided p-value of ≤0.05 was considered significant. Results: 588 patients completed LC. Median age at enrollment was 13.0 years (range: 0.6- 33.9 years). Tumor sites were categorized as extremity (230; 39%), axial (142; 24%), extraosseous (110; 19%), and pelvis (106; 18%). At diagnosis, tumor volume (TV) was ≥200 mL in 170 patients (31%) and maximum tumor dimension (MTD) was ≥8 cm in 289 patients (52%). LC was with S in 320 patients (54%), RT in 160 (27%), and S+RT in 108 (18%). Eight patients received preoperative RT. Fifty-three patients (13.1%) who received S±RT had an R1 resection. LC with S was more likely for extremity (58%), RT for pelvis (38%) and S+ RT for axial (36%) and extraosseous (34%) primary tumors (p <0.01). With median follow up of 67.6 months from LC, the 5-year cumulative incidences of LF and DF for the entire cohort were 6.0% (95% CI, 4.3-8.3%) and 11.0% (95% CI, 8.6-13.9%), respectively. Eleven patients experienced simultaneous LF and DF. LF incidence was 5.0% for S, 8.4% for RT, and 5.6% for S+RT (p=0.47). DF incidence was 11.8% for S, 6.4% for RT, and 15.1% for S+RT (p=0.16). LF incidence by tumor site was 3.6% for extremity, 8.7% for pelvis, 7.3% for axial, and 6.8% for extraosseous (p=0.08). LF incidence was higher for primary tumors ≥200 mL (11.3%) compared to tumors < 200 mL (3.9%; p<0.01) and for tumors ≥8 cm (7.8%) compared to tumors < 8 cm (4.4%; p=0.02). Tumor size was associated with a higher LF incidence for S and RT, but not for S+RT (Table). LF incidence was 4.0% for R0, 7.5% for R1 with RT, and 16.7% for R1 without RT (p=0.02). Conclusions: We report the lowest LF incidence to date for prospective ES trials conducted. Both larger TV and MTD were associated with higher LF. Future investigations will aim to evaluate the impact of chemotherapy dose-intensity on LC and identify risk-stratification variables for improved LC. Five-year LF incidence by LC and tumor size. Clinical trial information: NCT01231906 . [Table: see text]

10007 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1-21 years with relapsed or refractory solid tumors, CNS tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations in their tumor. Arm B (APEC1621B) evaluated the orally bioavailable FGFR inhibitor erdafitinib in patients whose tumors harbored activating alterations in FGFR 1/2/3/4. Methods: Patients received oral erdafitinib 4.7 mg/m 2 /dose (Max dose: 8 mg) daily for 28-day cycles until disease progression or drug related dose limiting toxicity (Max 26 cycles). Disease assessments were performed every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included progression free survival (PFS). Results: A total of 20 evaluable patients (median age: 15 yrs) were enrolled from June 2018 to July 2022 in this first study of erdafitinib in pediatric patients. The most common diagnosis (n = 17) was glioma or glioneuronal tumor (11 low grade and 6 high grade). Three patients had non-CNS solid tumors (1 each with neuroblastoma, osteosarcoma, and rhabdomyosarcoma). FGFR alterations detected consisted of activating hotspot mutations in FGFR1 (n = 16), FGFR2 (n = 1), FGFR4 (n = 1), and FGFR1 fusions (n = 2; FGFR1: TACC1, FGFR1: TACC3). Partial responses were confirmed by central review in 2/20 patients (10%, 90%CI: 3.4%, 26.2%), both with low grade gliomas or glioneuronal tumors (LGG, LGGNT) and FGFR1 hotspot mutations (K687E and N577K). A best response of stable disease (SD) was observed in 6 additional patients with gliomas with a median duration of SD of 6.5 cycles. Six-month PFS was 45% (95% CI: 23.1%, 64.7%) and six-month OS was 89.7% (95%CI: 64.8%, 97.3%). Treatment related adverse events included those previously reported with FGFR inhibitors including hyperphosphatemia and nail changes or infections. Grade 1 vision changes were also reported. There was one Grade 3 spinal cord compression and one Grade 4 intracranial hemorrhage. Conclusions: Erdafitinib was generally well tolerated in this heavily pre-treated cohort of children with relapsed tumors harboring FGFR alterations. Partial responses or stable disease were observed in the majority (6/11, 54%) of patients with FGFR1-mutant low grade gliomas or glioneuronal tumors, suggesting the possible benefit of FGFR inhibitor therapy for these patients. Further studies would be necessary to more thoroughly evaluate the activity of erdafitinib for patients with other histologies and FGFR alteration types or combination approaches that include other targeted and/or cytotoxic agents. Clinical trial information: NCT03210714 .

Abstract Background National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. Methods Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat. Results Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. Conclusions Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Abstract Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research. Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities. Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants. Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries. Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement.