Voss, Stephan D.

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 .

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 .

AbstractBackgroundInhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and adavosertib.MethodsPediatric patients with recurrent neuroblastoma (part B), medulloblastoma/central nervous system embryonal tumors (part C), or rhabdomyosarcoma (part D) were treated with irinotecan and adavosertib orally for 5 days every 21 days. The combination was considered effective if there were at least three of 20 responses in parts B and D or six of 19 responses in part C. Tumor tissue was analyzed for alternative lengthening of telomeres and ATRX. Patient's prior tumor genomic analyses were provided.ResultsThe 20 patients with neuroblastoma (part B) had a median of three prior regimens and 95% had a history of prior irinotecan. There were three objective responses (9, 11, and 18 cycles) meeting the protocol defined efficacy end point. Two of the three patients with objective responses had tumors with alternative lengthening of telomeres. One patient with pineoblastoma had a partial response (11 cycles), but parts C and D did not meet the protocol defined efficacy end point. The combination was well tolerated and there were no dose limiting toxicities at cycle 1 or beyond in any parts of ADVL1312 at the recommended phase 2 dose.ConclusionThis is first phase 2 clinical trial of adavosertib in pediatrics and the first with irinotecan. The combination may be of sufficient activity to consider further study of adavosertib in neuroblastoma.

AbstractImaging in hematopoietic stem cell transplantation patients is not targeted at evaluating the transplant per se. Rather, imaging is largely confined to evaluating peri‐procedural and post‐procedural complications. Alternatively, imaging may be performed to establish a baseline study for comparison should the patient develop certain post‐procedural complications. This article looks to describe the various imaging modalities available with recommendations for which imaging study should be performed in specific complications. We also provide select imaging protocols for different indications and modalities for the purpose of establishing a set minimal standard for imaging in these complex patients.

Abstract Purpose: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. Patients and Methods: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. Results: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. Conclusions: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

10022 Background: nab-Sirolimus (formerly know ABI-009 and nab-rapamycin) is a novel human albumin-bound preparation of sirolimus, a potent mTOR inhibitor. We report results of a Phase I study of ABI-009 alone and in combination with irinotecan and temozolomide in children with relapsed/refractory solid or CNS tumors. Methods: Patients (age 1-21 years) with relapsed/refractory solid or CNS tumors were eligible. Using a rolling 6 design, ABI-009 was administered intravenously as a single agent on Days 1 and 8 of cycle 1 (cycle = 21d), then subsequent cycles ABI-009 was administered in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) orally once daily x 5 on Days 1-5 and irinotecan 90 mg/m2/dose orally once daily x 5 on Days 1-5. Three dose levels (DL) of ABI-009 were investigated (DL1: 35mg/m2/dose, DL-1: 20mg/m2/dose, and DL-2: 15mg/m2/dose). The maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D) was established based on dose limiting toxicity (DLT) observed during Cycle 1 and 2. At the RP2D, additional patients were enrolled for pharmacokinetics (PK). Results: 33 patients were enrolled (32 eligible and 1 ineligible); 11 did not experience DLT but were not evaluable for toxicity due to progressive disease or physician decision to discontinue protocol therapy prior to completion of cycle 2; 17 [median age 13 (2-20) years] were evaluable for determination of MTD during dose escalation, 6 were enrolled on the PK cohort, of which 3 were evaluable to toxicity. At DL1, 2/5 patients experienced DLT (thrombocytopenia during cycle 1 (n = 1) and cycle 2 (n = 1)); at DL-1, 2/6 patients experienced DLT (thrombocytopenia in cycle 1); at DL-2, 1/6 patients experienced DLT (thrombocytopenia in cycle 1). PK expansion enrolled at DL-2 and 1/3 participants evaluable for toxicity had a DLT (mucositis). Overall, at DL-2, 2/9 patients (22%) had DLT. One patient with Ewing Sarcoma had a partial response and remained on study for 35 cycles; Patients (one each) with Ewing Sarcoma, Wilms Tumor, and Pineoblastoma had stable disease, ranging from 3-6 cycles. Conclusions: Thrombocytopenia was dose limiting for ABI-009 alone and in combination with temozolomide and irinotecan. The MTD for ABI-009 is 15mg/m2/dose days 1 and 8 in combination with 5 daily doses of temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose. One patient had a partial response, 3 patients had prolonged stable disease. Pharmacokinetics and pharmacodynamics are pending and will inform future trials. Clinical trial information: NCT02975882.

Abstract Introduction: Selinexor is a first-in-class, central nervous system (CNS) penetrant, oral inhibitor of exportin 1 (XPO1), the sole nuclear exporter of many key tumor suppressors. Selinexor is FDA-approved for refractory multiple myeloma and DLBCL and has been evaluated in a phase 1 trial in children with leukemia. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma (NCT02323880). Methods: A rolling-six design was used to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Dose determination was based on protocol-defined dose limiting toxicity (DLT) using CTCAEv4 during cycle 1. First dose pharmacokinetics (PK) were performed. Results: 43 subjects were enrolled (17 males); median (range) age was 15 (6-20) years. 27 (63%) had CNS tumors, most commonly high-grade glioma (n=12); 16 (37%) had extracranial solid tumors. 42 were evaluable for DLT. At the starting dose (35 mg/m2/dose, twice weekly), no DLTs were observed in 6 subjects, however, 2 subjects had unexpected late myelosuppression delaying initiation of cycle 2. The dosing schedule was amended to twice weekly for 3 weeks followed by a 1 week break. 12 subjects received 35 mg/m2/dose; 4 experienced DLTs [grade 3 fatigue (n=2), grade 3 thrombocytopenia (n=1), or grade 3 ALT increase (n=1)]. The dose was de-escalated to 20 mg/m2/dose, 3 weeks on, 1 week off. 12 subjects enrolled; 3 experienced a DLT [grade 3 increased AST/ALT, acute reversible neurologic changes, or neutropenia (each n=1)]. At the 20 mg/m2 (n=12) and 35 mg/m2 (n=19) dose levels, respectively, the mean ± SD Cmax (ng/ml) was 324±116 and 535±174, and AUC (hr•ng/ml) was 3092 ± 842 and 5156 ± 1227. This was comparable to PK in adults receiving 35 and 50 mg/m2. Based on a desire to achieve a higher Cmax and avoid breaks in schedule, and emerging evidence for similar effectiveness with decreased toxicity in adults receiving continuous once weekly dosing, we evaluated a dosing schedule with once weekly dosing for all 4 weeks of each cycle. At the initial dose level (45 mg/m2 weekly), 2 of 6 subjects had DLTs [prolonged grade 2 thrombocytopenia or grade 3 seizure in a primary CNS tumor patient]. Six subjects received 35 mg/m2/dose once weekly; 1 DLT [grade 3 thrombocytopenia] was observed. Non-dose-limiting toxicity (Grade ≥2 occurring in &gt;10% of subjects during cycle 1) included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. Subjects received a median (range) of 1 (1-9) cycle; 13 received 2-3 cycles, and 6 received 5-9 cycles. Conclusions: Selinexor-related toxicities were primarily hematological and gastrointestinal. The maximum tolerated dose (MTD) of selinexor in children and adolescents with recurrent solid and CNS tumors is 20 mg/m2/dose twice weekly for 3 weeks followed by one week off. On a continuous once weekly schedule, the MTD and recommended phase 2 starting dose of selinexor is 35 mg/m2/dose. Citation Format: Adam L. Green, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Kerice Pinkney, Stephan Voss, Marvin D. Nelson, Elizabeth Fox, Brenda J. Weigel, Julia Glade Bender. Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P162.

10010 Background: Cabozantinib is an inhibitor of multiple receptor tyrosine kinases (RTKs) including MET, VEGFR2, RET, and AXL. Preclinical and clinical data support these RTKs as potential therapeutic targets; Safety, tolerability, and responses were demonstrated in a COG phase 1 trial. We conducted a multi-center open label phase 2 trial to determine the activity of cabozantinib in select pediatric solid tumors (NCT02867592). Methods: Patients age 2-30 years old with selected relapsed or refractory cancer that was measurable (RECISTv.1.1) were eligible. Using a Simon minimax design, patients were enrolled to six strata: Osteosarcoma (OS), Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), Wilms tumor (WT), and rare tumor (a non-statistical stratum including tumors of specific histologies or molecular features). Cabozantinib (40 mg/m2/day) was administered on a continuous schedule (1 cycle = 28 days). For the OS stratum, activity was determined based on objective response rate (ORR, complete response (CR) + Partial response (PR)) or disease control success defined as at least stable disease (SD) for ≥ 4 months. For all other strata, the primary endpoint was ORR. Pharmacokinetics were performed in patients < 19 years. Results: Between May 2017- Oct 2020, 109 patients enrolled (105 eligible, 104 evaluable for response and toxicity). Median age was 15.8 (range 5.6-27.1) years; 55 were male. In the OS stratum, 10/29 (34%) patients had central review confirmed disease control ≥ 4 months (2 PR, 8 SD), exceeding the protocol-defined criteria for activity of cabozantinib in OS. Median duration of therapy was 3 cycles (range 1-28+). In EWS, RMS, NRSTS, and WT strata (n = 13 evaluable patients each) no PR or CR were observed. In the rare tumor stratum (n = 23), 1/4 patients with renal cell carcinoma, 1/1 patients with RET fusion positive papillary thyroid cancer had a PR, and 1 patient with medullary thyroid cancer had a delayed PR. SD ≥ 6 cycles was seen in patients with EWS (n = 2), NRSTS (n = 5), WT (n = 3), and hepatocellular carcinoma (n = 1). At data cutoff (12/31/2020), 430 treatment cycles were administered; two patients remain on therapy. Cycle 1 and later cycle dose limiting toxicities (DLT) were seen in 20 (19%) and 39 (38%) patients, respectively. Common DLT were elevated liver enzymes, bilirubin, and lipase, hyponatremia, weight loss, anorexia, nausea, vomiting, wound dehiscence, palmar-plantar erythrodysesthesia, and pneumothorax. Day 1 pharmacokinetics (mean ± SD, n = 16) demonstrated a maximum plasma concentration of 556 ± 376 ng/ml, half-life 106 ± 102 hours, and area under the curve (AUC0-24h) 8093 ± 4368 ng•h/mL. Conclusions: Cabozantinib is active in patients with relapsed refractory OS and deserves further study in this disease. PRs were also seen in select carcinomas. Activity is limited in other sarcomas and WT. Clinical trial information: NCT02867592.