Citations

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 .

5606 Background: The National Comprehensive Cancer Network (NCCN) recommends that patients with endometrial cancer under age 50 undergo germline genetic testing. Despite this recommendation, completion rates are suboptimal for patients with gynecologic malignancies. The reasons for failure to complete testing are unknown, but oncology providers may not refer patients to genetic counselors, who frequently order this testing. Best practice advisories (BPAs) in electronic medical records can alert providers of patients who meet guideline-based treatments and testing criteria. It is unknown how oncology providers interact with a BPA indicating patients with endometrial cancer meet NCCN germline testing criteria. The objective of this study is to evaluate genetic counseling referral patterns after implementing a BPA. Methods: Our team developed a BPA to prompt oncology providers to order genetic counseling referrals for patients diagnosed with endometrial or uterine cancer under age 50. We reviewed all provider-BPA interactions between go-live (January 2022) and January 2023. Patient demographic, histopathologic, and cancer treatment data were collected. Provider actions, including BPA cancellation and order placement, were collected. The Chi-Square goodness of fit test was used to identify differences in referral rates by patient or disease characteristics. Results: The BPA displayed 1121 times for 103 patients. Attending physicians received 535 alerts, fellow physicians – 269, and advanced practice providers (APPs) – 317. The median number of alerts per patient was 7 (range 1-87). Of the 103 patients, 23 were excluded from analysis due to no diagnosis of endometrial cancer, patient declined referral, previously completed, or a lack of provider visits within the study period. Of the 80 eligible patients, 36 (45%) received referrals; 18 were placed by attending physicians, 17 by fellows, and one by an APP. Patients under age 40 versus age 40-49 were more likely to be referred (65% vs. 35%; p = 0.011). Patients with active disease were more likely to be referred than those in surveillance (65% vs. 18%; p < 0.001). There were no differences in referral rates by primary language, race, body mass index ≥40, fertility-sparing versus definitive treatment, stage I versus stage II-IV disease, or grade 1-2 versus three tumors. Conclusions: Despite implementing a BPA, only 45% of eligible patients received indicated referrals. Attending and fellow physicians frequently manage patients with active disease and often order referrals; however, APPs frequently manage patients in surveillance and infrequently place referrals, highlighting an opportunity for education. In addition, patients aged 40-49 are less likely to be referred, suggesting a need for new strategies to improve referral rates. Further research is indicated to identify referral barriers for patients undergoing active treatment.

2517 Background: Approximately 50% to 60% of pts with r/r LBCL will either not achieve a complete response (CR) or will relapse with current treatments and require additional therapy. Autologous anti-CD19 chimeric antigen receptor T (CAR T) therapies have revolutionized the care of patients whose disease progresses following standard therapies, but patient-specific manufacturing processes and long wait times to treatment present challenges for their broad clinical use. Allogeneic (healthy-donor-derived), off-the-shelf, anti-CD19 (CAR T) treatment promises broader and more rapid access to one-dose treatment with curative intent. Initial phase 1 data for the anti-CD19 AlloCAR T cell product ALLO-501 (NCT03939026) and successor, ALLO-501A (NCT04416984), demonstrated a manageable safety profile with no dose-limiting toxicities (DLTs), and efficacy comparable to autologous CAR T therapy in pts with r/r LBCL who were autologous CAR T-naïve. This update provides additional follow up and a focus on participants who received the conditioning regimen and cells made with an optimized manufacturing process currently under study in the first potentially pivotal trial for an allogeneic CAR T product. Methods: In these two multicenter, single-arm, open-label, phase 1 trials, a cohort of autologous CAR T-naïve pts with r/r LBCL underwent 3-day lymphodepletion (LD) with FCA90, fludarabine (F, 30 mg/m2/day), cyclophosphamide (C, 300 mg/m2/day), and ALLO-647 (A [anti-CD 52 mAb] 30 mg/day; total dose: 90 mg) followed by a single dose of ALLO-501 or ALLO-501A produced by the Alloy manufacturing process. Results: As of Jan 26, 2023, 12 pts received the FCA90 LD regimen and CAR T therapy with 100% receiving product per specifications with a median time from enrollment to LD of 3 days. Median follow-up time (actual) was 7.1 months (range: 1.4, 36.0). No DLTs, severe (Gr3+) cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) events occurred. An overall response rate and a CR rate of 66.7% and 58.3%, respectively, were observed. Median DOR was 23.1 months. Among 8 pts with the opportunity to be followed for 6 months, 5 (62.5%) had achieved CR and 4 (50.0%) sustained CR through 6 months. Analyses of vector copy number pharmacokinetics at Days 28 and 56 documented substantial and sustained expansion of CAR T cells. Conclusions: A one-time dose of allogeneic CAR T therapy following LD with FCA90 provided durable responses with a manageable safety profile in patients with r/r/ LBCL comparable to those treated with autologous CAR T cells. This treatment enables rapid access to off-the-shelf treatment with a median time from trial enrollment to treatment of 3 days. These findings support broader evaluation of ALLO-501A in the ongoing, first potentially pivotal phase 2 trial (ALPHA2) of off-the-shelf allogeneic CAR T cells. Clinical trial information: NCT03939026 .

TPS2084 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with IV microbubble oscillators (DEFINITY), non-invasively causes BBB disruption (BBBD). This clinical trial aims to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. Methods: LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged >18-80 years with suspected GBM planned for tumor biopsy or resection at eleven centers in North America are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. Patient enrollment commenced in 2022 and 7 patients have been recruited by 02/13/2023. Clinical trial information: NCT05383872 .

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 .

2017 Background: Response Assessment in Neuro-Oncology (RANO) criteria for high-grade and low-grade glioma (HGG and LGG) were developed to improve reliability of response assessment in glioma trials. Several limitations of the original RANO criteria have been reported. Methods: To address limitations of the original RANO criteria, a large cohort of patients with newly diagnosed and recurrent glioblastoma were evaluated comparing RANO-HGG with modified RANO (mRANO) and immunotherapy RANO (iRANO) criteria to inform the following proposed updates (RANO 2.0). Results: Based on the 2021 WHO classification of glioma, we recommend a single common set of criteria for all gliomas regardless of WHO grade and IDH mutational status. These criteria will be used for all trials regardless of the treatment modalities being evaluated. In newly diagnosed glioblastoma, the post-radiotherapy MRI, usually obtained approximately 4 weeks after completion of radiotherapy, rather than the post-surgical MRI as proposed in original RANO criteria, will be used as the baseline for comparison of subsequent scans. Since the incidence of pseudoprogression is high in the first 3 months following radiotherapy, confirmation of progression during this period with a repeat MRI (in 4-8 weeks) will be required for determining radiographic progression of disease (PD) if the patient is clinically stable. However, confirmation scans are not mandatory after this period nor for recurrent tumors since these scans do not appear to improve reliability in determining progression. For agents with a high likelihood of producing pseudoprogression such as viral therapies and some other immunotherapies, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement will remain the 2-dimensional maximum cross-sectional area of tumor as the simplest method, but where resources are available, volumetric measurements are an option. For IDH wild-type tumors with contrast enhancement, non-enhancing tumor will no longer be evaluated with the possible exception of patients receiving antiangiogenic therapies. However, in tumors with a significant non-enhancing component, both the contrast enhancing and non-enhancing components will be evaluated as target lesions. Conclusions: We hope that these and other proposed changes by the RANO working group will improve response assessment in glioma clinical trials and help the development of more effective therapy for patients.

AbstractSomatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged between &lt;1 month and 88 years treated on Children’s Cancer Group/Children’s Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): pediatric (0-17, 1744), adolescent/young adult (18-39, 444), intermediate-age (40-59, 640), older (≥60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (n = 288; IDH1 [n = 123, 42.7%]; IDH2 [n = 165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P &lt; .001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P = .368; overall survival [OS]: 50.3% vs 55.4%, P = .196). IDH mutations frequently occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-internal tandem duplication (ITD) (22.4%) mutations. Patients with IDHmut AML with NPM1 mutation (IDHmut/NPM1mut) had significantly improved survival compared with the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P &lt; .001; OS: 66.5% vs 35.2%, P &lt; .001). DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Age group analysis demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients aged &lt;60 years; older patients had poor outcomes regardless of NPM1 status. These trials were registered at www.clinicaltrials.gov as #NCT00070174, #NCT00372593, #NCT01371981, #NCT00049517, and #NCT00085709.

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.

Background: Our understanding of the risk factors for and effectiveness of prophylactic measures against shoulder periprosthetic joint infections (PJIs) continues to evolve. This study’s objective was to study patient characteristics, procedural characteristics, and various infection prophylactic measures and their effects on the risk of shoulder PJI after primary arthroplasty. Methods: Nine hundred and ninety-eight patients in a longitudinally maintained, single-institution shoulder arthroplasty database who had at least 2 years of clinical follow-up were retrospectively reviewed. Patient and procedural characteristics were collected. Perioperative variables, including the use of intraoperative antibiotics, topical antibiotics, antibiotic-containing irrigation solution, and a postoperative drain, were collected. Patients who developed shoulder PJI were compared with those without shoulder PJI to identify any association with patient or procedural characteristics. Results: Of the 998 patients, 20 (2.0%) met the criteria for shoulder PJI. Cutibacterium was identified as the causative organism in 19 (95%) of 20 culture-positive reoperations. On univariate analysis, patients in the PJI group were more likely to be younger (p < 0.001), to be male (p = 0.014), to have commercial insurance (p = 0.003), to use alcohol (p = 0.048), and to have had a ream-and-run or hemiarthroplasty procedure (p = 0.005). On multivariable analysis, older age was independently associated with a lower risk of PJI (odds ratio [OR] per year = 0.95; 95% confidence interval [CI], 0.91 to 0.99; p = 0.014). Reverse total shoulder arthroplasty (OR, 10.32; 95% CI, 0.92 to 116.33; p = 0.059) and hemiarthroplasty (OR, 8.59; 95% CI, 0.86.30 to 85.50; p = 0.067) trended toward a higher risk of PJI. Conclusions: Younger patients and patients undergoing procedures other than anatomic total shoulder arthroplasty are at higher risk for shoulder PJI. The majority of culture-positive reoperations were a result of Cutibacterium species. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.