Weigel, Brenda J.

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.

AbstractBackgroundPrexasertib (LY2606368) is a novel, second‐generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum‐tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors.MethodsPrexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28‐day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2, were evaluated using a rolling‐six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity.ResultsThirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2‐20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose‐limiting toxicities. Common cycle 1, drug‐related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80‐150 mg/m2 dose range.ConclusionsAlthough the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28‐day cycle was determined to be the RP2D.

AbstractBackgroundEntinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies.MethodsA rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28‐day cycle. PK and PD studies were performed.ResultsTwenty‐one eligible patients’ median (range) age was 14 years (6‐20). Six subjects were treated at 3 mg/m2dose level and 15 were treated in 4 mg/m2dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose‐limiting toxicity (DLT) was observed at either dose level. A three‐fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses.ConclusionsEntinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2orally administered once weekly.

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children's Oncology Group (COG) AINV18P1 trial are reported. Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population. Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing. Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial. Disclosures Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey:La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris:Merck: Other: Travel funding. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.

Background Lorvotuzumab mertansine (IMGN901) is an antibody‐drug conjugate linking an antimitotic agent (DM1) to an anti‐CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities. Methods Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m 2 per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21‐day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56‐positive cell counts, and tumor CD56 expression were assessed. Results Sixty‐two patients enrolled. The median age was 14.3 years (range, 2.8‐29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose‐limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non–dose‐limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half‐life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response. Conclusions Lorvotuzumab mertansine (110 mg/m 2 ) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.

TPS10560 Background: In children, fusions of the NTRK1/2/3 genes (TRK fusions) occur in soft tissue sarcomas, including infantile fibrosarcoma (IFS), congenital mesoblastic nephroma, high- and low-grade gliomas, secretory breast carcinoma, and papillary thyroid cancer. Rarely, TRK fusions also occur in Ph-like acute lymphoblastic leukemia and acute myeloid leukemia. Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. In children, larotrectinib demonstrated a 94% overall response rate (ORR) with a 12-month progression free survival rate of 75% (1). Methods: Patients <30 years with any newly diagnosed unresectable solid tumor or relapsed/refractory acute leukemia with TRK fusions are eligible. TRK fusions must be locally identified in a CLIA/CAP laboratory and are confirmed centrally using a targeted RNA sequencing panel. Patients with high-grade gliomas are excluded. Patients receive larotrectinib 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles. Patients with solid tumors who achieve CR will discontinue larotrectinib at the completion of at least 12 total cycles of therapy and 6 cycles after achieving CR. Those whose tumors become surgically resectable may undergo on study resection and discontinue therapy if an R0/R1 (IFS) or R0 (other tumors) resection is obtained. All other patients will receive 26 cycles in the absence of unacceptable toxicity or progressive disease. The primary endpoint is the ORR to larotrectinib according to RECIST 1.1 in children with IFS. The study uses a Simon 2-stage minimax design, and the regimen will be considered of sufficient interest if 16 of 21 (76%) patients with IFS demonstrate response. Patients with other solid tumors and leukemias will be analyzed in separate cohorts as secondary objectives. Correlative studies include serial sampling of circulating tumor DNA and neurocognitive assessments. This is the first Children’s Oncology Group study to assign frontline therapy based on the presence of a molecular marker independent of histology, and the first clinical trial to evaluate larotrectinib for the treatment of leukemia. Enrollment began in October 2019 (NCT03834961). 1. Tilburg CMv, DuBois SG, Albert CM, et al: Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients. Journal of Clinical Oncology 37:10010-10010, 2019 Clinical trial information: NCT03834961.

AbstractInfantile myofibromatosis (IM) is characterized by solitary musculoskeletal nodules presenting during infancy but can manifest as multiple lesions with visceral involvement. Multicentric IM with visceral involvement carries a high risk of mortality and there is no consensus on treatment. We present a case of a patient with multicentric IM and pulmonary involvement who progressed on several chemotherapeutic regimens and subsequently had a complete response to sorafenib and later imatinib. This report describes the novel use of sorafenib and imatinib to treat generalized IM and the role of continued tyrosine kinase inhibitor therapy to maintain remission.

e21521 Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 (20mg/m2), and 3 (25mg/m2). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.

e21519 Background: Semaphorins regulate tumor progression, immune responses, and angiogenesis. SEMA4D was identified as a candidate proto-oncogene by a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice. SEMA4D is expressed on tumors, including osteosarcoma, and in the tumor microenvironment. VX15/2503, a humanized IgG4 monoclonal antibody, binds SEMA4D, blocks receptor interaction and enhances the anti-tumor immune response in preclinical studies. This trial aimed to determine the tolerability and recommended dose of VX15/2503 in patients with relapsed/refractory solid tumors and activity in patients with osteosarcoma. Methods: Part A enrolled patients age≤ 21y with refractory solid tumors to assess the tolerability of VX15/2503 (20 mg/kg) IV every 14 days x 2 doses/cycle. The recommended dose was one that was tolerated and achieved sustained target saturation. Up to 6 additional children were enrolled to assess pharmacokinetics (PK). In part B, a two-stage design was used to assess the activity of VX15/2503 in patients with measurable, relapsed /refractory osteosarcoma. In part B1 patients > 21-30y accrued concurrently with part A; Part B2 (patients £ 21y) was initiated after the pediatric recommended dose was determined. Correlative studies including target saturation by VX15/2503 were required. Results: 18 eligible patients enrolled, 16 evaluable for toxicity. In part A (n = 12) the median (range) age was 12.5 (1-20) y. Diagnoses included osteosarcoma (8), neuroblastoma (2), other (2). No dose limiting toxicities (DLTs) were observed. In Part B1, (n = 6) median (range) age was 22.5 (22-30) y; one patient had cycle 1 DLTs (grade 3 acute kidney injury, creatinine increase, arthralgia and myalgia); a second patient had a later cycle DLT (grade 4 pericardial effusion). Given only 1/18 had a cycle 1 DLT, this did not impact dose selection. T-cell saturation by VX15/2503 was adequate and sustained in all patients. Conclusions: VX15/2503 was well tolerated at 20 mg/kg IV every 2 weeks and is the recommended dose in children, adolescents and young adults. The activity in osteosarcoma is under evaluation. Future trials combining VX15/2503 with novel agents are in development. Clinical trial information: NCT03320330.

2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.