First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients
Robert C. Castellino, Hope Mumme, Andrea Franson, Bing Yu, Hope Robinson, Kavita Dhodapkar, Dolly Aguilera, Matthew Schniederjan, Rohali Keesari, Zhulin He, Manoj Bhasin, Waldemar Priebe, Amy B. Heimberger, Tobey J. MacDonald
Robert C. Castellino, Hope Mumme, Andrea Franson, Bing Yu, Hope Robinson, Kavita Dhodapkar, Dolly Aguilera, Matthew Schniederjan, Rohali Keesari, Zhulin He, Manoj Bhasin, Waldemar Priebe, Amy B. Heimberger, Tobey J. MacDonald
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Clinical Research and Public Health Clinical Research Oncology

First-in-child phase I trial of p-STAT3 inhibitor WP1066 in pediatric brain tumor patients

Abstract

BACKGROUND WP1066 is an orally bioavailable, small-molecule inhibitor of activated phosphorylated STAT3 (p-STAT3) that has demonstrated preclinical efficacy in pediatric brain tumor models.METHODS In a first-in-child, single-center, single-arm 3+3 design phase I clinical trial, 10 patients were treated with WP1066 twice daily, Monday-Wednesday-Friday, for 14 days of each 28-day cycle to determine the maximum tolerated dose/maximum feasible dose of WP1066. Compassionate-use treatment with WP1066 in 3 pediatric patients with H3.3G34R/V-mutant high-grade glioma (HGG) is also described.RESULTS There was no significant toxicity, and the maximum feasible dose (MFD) was determined to be 8 mg/kg. Treatment-related adverse events were grade 1–2 (diarrhea and nausea most common); there were no dose-limiting toxicities. Median progression-free and overall survival was 1.8 months and 4.9 months, respectively. One partial response was observed in a patient with pontine glioma. Among the H3.3G34R/V-mutant HGG patients not on study, WP1066 was administered after upfront radiation to one patient for 17 months. At all dose levels tested, WP1066 suppressed p-STAT3 expression by peripheral blood mononuclear cells (PBMCs). Single-cell RNA sequencing analysis of PBMCs demonstrated increased CD4+ and CD8+ T cells, proinflammatory TNFA signaling, differentiation activity in myeloid cells, and downregulation of Tregs after WP1066 treatment, consistent with systemically inhibited STAT3 activity.CONCLUSION WP1066 is safe, has minimal toxicity, and induces antitumor immune responses in pediatric brain tumor patients. Phase II investigation of WP1066 at the MFD in this patient population is warranted.TRIAL REGISTRATION ClinicalTrials.gov NCT04334863.FUNDING CURE Childhood Cancer and Peach Bowl Inc.

Authors

Robert C. Castellino, Hope Mumme, Andrea Franson, Bing Yu, Hope Robinson, Kavita Dhodapkar, Dolly Aguilera, Matthew Schniederjan, Rohali Keesari, Zhulin He, Manoj Bhasin, Waldemar Priebe, Amy B. Heimberger, Tobey J. MacDonald

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Figure 6

Changes in T cell subsets in response to WP1066.

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Changes in T cell subsets in response to WP1066. CD4+ and CD8+ T cell su...
CD4+ and CD8+ T cell subsets were estimated using phenotype signatures from the literature and assessing the expression of these signatures in T cell subsets in PBMCs. PBMCs analyzed correspond to the PBMC samples analyzed by flow cytometry demonstrating suppressed p-STAT3 after WP1066 treatment (AflacST1901-04, -05, -06, -07, -08) and one additional subject (AflacST1901-010) who did not have flow cytometric analysis for PBMC p-STAT3. Only subject AflacST1901-010 received concomitant corticosteroids during treatment, and the dosage of steroids administered remained constant throughout. Module score function from Seurat was used to represent the aggregate expression of these signatures in the cells. (A and B) Module scores for CD4+ (A) and CD8+ (B) naive signatures are shown for the designated time points. (C and D) Module scores for Treg signature (C) and CD8+ T cell exhaustion signature (D) are shown. Wilcoxon’s rank sum tests were used to compare module scores for cells from C1D1 versus C1D8 and C1D8 versus C2D1 time points. The resulting P values are shown: ****P < 0.0001; ns, not significant, P > 0.05. (E) Differential expression analysis was performed to identify genes significantly changing in expression in T and NK cells between C1D1 and C1D8 time points. Genes increasing after treatment (UP @ C1D8, purple) were identified based on the adjusted P value and average log2(fold change) [log2(FC)] results [adjusted P value < 0.05, average log2(FC) > 0.25]. DEG, differentially expressed gene.