Takebe, Naoko

3009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 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 J evaluated the ERK1/2 inhibitor ulixertinib (BVD-523FB) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAPK1, MAP2K1, GNA11, GNAQ hotspot mutations; NF1inactivating mutations; BRAF fusions). Methods: As there were no prior pediatric data, ulixertinib was initially tested in a dose escalation cohort using a rolling 6 design to establish the recommended phase 2 dose (RP2D) before proceeding with enrollment to the phase 2 cohort. Ulixertinib was administered at 260 mg/m2/dose PO BID (dose level 1, DL1, n = 15) or 350 mg/m2/dose PO BID (dose level 2, DL2, n = 5). Patients were treated on continuous 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 rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty patients (median age 12 years; range 5-20) were enrolled between November 2018 and March 2021. All patients were evaluable for response. High-grade glioma (HGG, n = 7) was most common, with CNS tumors comprising 55% (11/20) of diagnoses; all CNS tumors except one (HGG with KRAS and NF1 mutations) harbored BRAF fusions or V600 mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis, with NRAS mutations detected in 4 tumors. DL1 was declared the RP2D after first-cycle dose limiting toxicities (DLTs) occurred in 1/6 DLT-evaluable patients at DL1 and 2/5 patients at DL2 in the dose escalation cohort. Any-cycle DLTs in 8 patients in the dose escalation and primary cohorts included fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, increased creatinine, hypoalbuminemia, hypernatremia, and hip fracture. No objective responses were observed. Six-month PFS was 37% (95% CI: 17%, 58%). Three patients with CNS tumors achieved stable disease > 6 months (HGG with BRAF fusion, 15 cycles; glioneuronal tumor with BRAF V600E, 9 cycles; low-grade glioma with BRAF fusion, 7 cycles). Analyses of correlative studies, including pharmacokinetics and circulating tumor DNA, are ongoing. Conclusions: The pediatric RP2D of ulixertinib was established as 260 mg/m2/dose PO BID. There were no objective responses in this cohort of children and young adults with treatment-refractory tumors with activating MAPK alterations. Clinical benefit of prolonged disease control was observed in 3 patients with BRAF-altered gliomas and glioneuronal tumors. Clinical trial information: NCT03698994.

PURPOSE The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib. METHODS Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib. RESULTS Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG ( NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug. CONCLUSION A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.

AbstractThe purpose of this study was to develop and validate a population pharmacokinetic model for Z‐endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z‐endoxifen‐HCl was administered orally once a day on a 28‐day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z‐endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed‐effects modeling to develop a population pharmacokinetic model for Z‐endoxifen. A 2‐compartment model with oral depot and linear elimination adequately described the data. The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 4.89 L/h, 323 L, and 39.7 L, respectively, with weight‐effect exponents of 0.75, 1, and 1, respectively. This model was used to explore the effects of clinical and demographic variables on Z‐endoxifen pharmacokinetics. Weight, race on clearance, and aspartate aminotransferase on the absorption rate constant were identified as significant covariates in the final model. This novel population pharmacokinetic model provides insight regarding factors that may affect the pharmacokinetics of Z‐endoxifen and may assist in the design of future clinical trials.

10008 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 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 E evaluated the MEK inhibitor selumetinib (ARRY-142886) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAP2K1, GNA11, GNAQ hotspot mutations; NF1 inactivating mutations; BRAF fusions). Methods: Patients received selumetinib 25 mg/m2/dose (max 75 mg/dose) PO BID for 28-day cycles until disease progression or intolerable toxicity with response assessments obtained every 2-3 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS). Patients with low grade glioma were excluded. Results: A total of 21 patients (median age 14 years; range 5-21) were enrolled between 10/2017 and 8/2019, with 20 patients evaluable for response. Diagnoses were high grade glioma (HGG; n = 8), rhabdomyosarcoma (n = 7), adenocarcinoma (n = 2), and one each of MPNST, endodermal sinus/yolk sac tumor, plexiform neurofibroma (PN), and neuroblastoma. MAPK pathway alterations detected consisted of inactivating NF1 mutations (n = 8), hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease (HGG with NF1 mutation, 6 cycles; HGG with KRAS mutation, 12 cycles; PN with NF1 mutation, 13 cycles prior to removal for dose-limiting toxicity). Six-month PFS was 15% (95% CI: 4%, 34%). Adverse events that were deemed possibly, probably, or definitely attributable to study drug included one case each of grade 3 uveitis, lymphopenia, and thromboembolic event; one grade 4 CPK elevation; and one grade 5 thromboembolic event. Conclusions: Selumetinib did not result in tumor regression in this cohort of children and young adults with treatment-refractory tumors with activating MAPK pathway alterations. Of note, two patients with HGG initially had stable disease, but ultimately progressed after 6 and 12 cycles, respectively. Selumetinib has previously demonstrated activity in low grade glioma and PN and is now FDA-approved for PN. The results of our study indicate that MAPK pathway mutation status alone is insufficient to predict response to selumetinib monotherapy. It is likely that selumetinib and other MEK inhibitors will require combination with targeted or cytotoxic agents for optimal efficacy in children with persistent or progressive cancers after front-line chemotherapy. Clinical trial information: NCT03213691. Clinical trial information: NCT03155620.

Abstract Prior in vitro work in the human hepatoma cell lines Huh7 and HEP3B indicated that combination treatment of the BH3 mimetic, navitoclax, and the multi-kinase inhibitor, sorafenib, was more effective at inducing apoptosis than either compound alone. This current study was part of a phase I clinical trial to determine the maximum tolerated dose of concurrent navitoclax and sorafenib treatment in patients with relapsed or refractory solid organ tumors and sought to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of both agents in combination. Cleavage of cytokeratin 18 by caspase 3 was used as a biomarker for therapy-induced activation of apoptosis to determine if combination treatment results in an increase in apoptosis as previously observed in in vitro work. PK were assessed in 26 patients (ages 32 - 80) enrolled in a phase I clinical trial (NCT02143401). 150 mg of oral navitoclax was administered once daily for a seven day run-in (beginning Day -7) prior to 150 mg (Dose level 1) or 200 mg (Dose level 2) navitoclax concomitant treatment with 400 mg of twice daily oral sorafenib (Day 1). Samples for pharmacokinetic analysis were obtained on Day -7 and Day 1 prior to dosing and at 1, 2, 4, 8-12, and 24 hours post dosing. PK parameters were estimated by noncompartmental analysis using Phoenix® WinNonlin® Version 6.4. To examine the PD of both agents in combination, cytokeratin 18 cleavage was quantified by ELISA after the 7-day navitoclax run-in and on Day 2 or 4 and Day 8 of navitoclax and sorafenib combination treatment. PK estimates of maximum concentration, exposure, volume of distribution, and clearance for navitoclax on Day -7 and Day 1 were not significantly different, indicating a lack of navitoclax accumulation. Finally, no correlation was found between navitoclax exposure and apoptosis as indicated by cytokeratin-18 cleavage. This work was supported by the NCI Cancer Center Support Grant P30 CA15083 and NCI Experimental Therapeutics Phase I Grant UM1 CA186686. Citation Format: Emily J. Koubek, Brian A. Costello, Jun Yin, Renee M. McGovern, Sarah A. Buhrow, Renee A. Schoon, Carrie A. Strand, Yixing Jiang, Mitesh J. Borad, Naoko Takebe, Scott H. Kaufmann, Alex A. Adjei, Joel M. Reid. Pharmacokinetic analysis of navitoclax in combination with sorafenib in patients with relapsed or refractory solid organ tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT114.

Abstract Background The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. Methods Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial. Results At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). Conclusions The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.