Fox, Elizabeth

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.

AbstractPurposePepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high‐affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low‐affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T‐cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto‐oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma.Experimental designPepinemab was administered intravenously on Days 1 and 15 of a 28‐day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2‐stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood.ResultsPepinemab (20 mg/kg) was well tolerated and no dose‐limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults.ConclusionsPepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response.Clinical trial registryThis trial is registered as NCT03320330 at Clinicaltrials.gov.DisclaimerThe content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

AbstractBackgroundRamucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR‐2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min) ≥ 50 µg/mL was established.ProceduresThis phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned.ResultsTwenty‐nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1–21] years; 22 were evaluable for the PK endpoint. Dose‐limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin ≥ 50 µg/mL.ConclusionRamucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.

AbstractBackgroundOutcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD‐8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.ProcedureWe evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m2 days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza‐FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1–21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy‐related AML (n = 1).ResultsOverall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) Cmax, VSS, T1/2, and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m2, 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m2, respectively. T1/2, VSS, and Cmax, but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi).ConclusionsPevonedistat 20 mg/m2 combined with Aza‐FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza‐FLA combination demonstrated significant anti‐leukemic activity.

Abstract Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6‐cyclin D complex that regulates cell cycle progression. Procedure The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four‐drug re‐induction chemotherapy in children and young adults with relapsed/refractory B‐ and T‐cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1–3) and subsequently combined with re‐induction chemotherapy. This two‐part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose‐limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T‐ALL and three among seven patients with B‐ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with re‐induction chemotherapy was well tolerated with a RP2D of 50 mg/m 2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

10008 Background: NTRK1/2/3 gene fusions (TRK fusions) occur in a range of pediatric cancers and are the canonical molecular alterations in IFS. Larotrectinib is a highly selective TRK inhibitor that is FDA-approved for TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. ADVL1823 (NCT03834961) evaluated larotrectinib in children with newly diagnosed TRK fusion positive solid tumors in two histology-based cohorts. Cohort A enrolled patients with IFS and is the focus of this analysis. Methods: Newly diagnosed patients ≤30 years old with unresectable or metastatic IFS and a locally identified NTRK gene fusion were eligible for Cohort A utilizing a Simon 2-stage design. Patients received larotrectinib at a dose of 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles until disease progression, unacceptable toxicity, the tumor becoming surgically resectable following a minimum of 6 cycles of therapy, or completion of 12 cycles (for those with CR) or 26 cycles (for those with PR) of therapy. The primary endpoint was the centrally confirmed objective response rate within 6 cycles according to RECIST 1.1; response assessment occurred every 2 cycles for the first 6 cycles. The data cutoff was December 31, 2022. Results: Between October 2019 and May 2022, 18 patients with IFS were enrolled from 14 centers. The median age was 2 months (range <1 month to 4.6 years). NTRK fusions included presumed/confirmed ETV6: NTRK3, n=15, NTRK3 (partner unconfirmed), TMP3: NTRK1 and DCTN1: NTRK1, n=1 each, and were identified by FISH (n=8), NGS (n=7), and PCR (n=3). 17 of 18 patients (94%) demonstrated confirmed objective responses (16 PR and 1 CR,) resulting in closure to enrollment after meeting the pre-specified efficacy threshold. The only patient without confirmed response demonstrated 79% tumor reduction after cycle 2, but no confirmatory scan was obtained within the first 6 cycles. No patient discontinued therapy within the first 6 cycles due to disease progression or toxicity. Four (22%) patients had dose limiting toxicities: 2 neutropenia (both CTCAE V5 grade (G)4) and 1 each G3 AST increase and G3 weight loss. All patients resumed therapy following a dose reduction. Treatment-related grade ≥ 3 toxicities occurred in 7 patients, most commonly neutropenia (n=5, 3 G3, 2 G4). Conclusions: Larotrectinib is highly active and well tolerated in newly diagnosed patients with IFS. Enrollment of this very rare molecularly defined patient population was feasible within the COG. Ongoing follow-up will evaluate durability of response after treatment discontinuation at protocol specified response-adapted timepoints with or without surgical resection of tumor. Clinical trial information: NCT03834961 .

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 .

e15131 Background: Elimusertib is a highly selective oral inhibitor of the Ataxia telangiectasia and Rad3 related (ATR) kinase, which is required for efficient end-joining repair of double-stranded breaks, particularly during DNA replication. Many pediatric cancers involve potential ATR susceptibilities such as increased replication stress due to oncogenic fusions, specific DNA damage repair (DDR) deficiencies, oncogenic activation of DNA damage and nucleases such as PGBD5, as well as alternative lengthening of telomeres. We report the initial phase 1 results of PEPN2112 (NCT05071209), an ongoing pediatric phase 1/2 clinical trial of elimusertib monotherapy. Methods: Eligible patients (pts) included children, adolescents, and young adults with relapsed or refractory tumors with: (1) Ewing sarcoma or related EWSR1 fusion positive tumors (EWS), (2) alveolar rhabdomyosarcoma, PAX3-FOXO1 fusion positive (aRMS), or (3) non-CNS primary tumors exhibiting specific DDR pathway defects anticipated to sensitize to ATR inhibition. For pts < 18 years (yrs), a rolling-six design was used to evaluate elimusertib administered BID x3 days/week of a 28-day cycle starting at the adult equivalent recommended phase 2 dose (RP2D) of 24 mg/m2/dose (max 40 mg) with a potential de-escalation to 18 mg/m2/dose (max 30 mg). The pediatric RP2D determination was based upon dose limiting toxicity (DLT) criteria (CTCAEv5) during cycle 1. Pharmacokinetic (PK) studies were performed. Pts > 18 yrs could enroll onto the phase 2 cohorts at the adult RP2D simultaneously with the pediatric phase 1. Once the pediatric RP2D was defined, pts < 18 yrs accrued to the phase 2 cohorts and a PK expansion for pts < 12 yrs was opened. Results: 8 eligible pts were enrolled (4 males) on the phase 1 part of the study. 2 pts were inevaluable for DLT as they received < 75% of protocol therapy. Median (range) age was 13 (10-17) yrs. Diagnoses included: EWS (n = 4) and 1 pt each with aRMS, adrenocortical carcinoma, clear cell sarcoma, and osteosarcoma. At 24 mg/m2/dose, no DLTs were observed. Toxicities were hematologic, with grade 3 toxicities including anemia (n = 3), neutropenia (n = 4), and decreased white blood cells (n = 1). One pt experienced grade 4 lymphopenia. There were no grade 3/4 non-hematologic toxicities. Day 1 mean ± SD values of Tmax, Cmax, AUC0-8h and t1/2 were 1.6 ± 0.5 h, 1532 ± 385 ng/mL, 5863 ± 1841 h*ng/mL and 3.6 ± 0.9 h, respectively. Conclusions: Elimusertib-related toxicities were primarily hematologic. The RP2D for elimusertib monotherapy in pediatric pts is 24 mg/m2/dose (max 40 mg) orally BID x3 days/week continuously, analogous to dosing in adults with similar PK. Phase 2 and PK expansion cohorts as well as pharmacodynamic studies are ongoing. Clinical trial information: NCT05071209 .

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 .