A first-in-human Phase i trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma

• Type of Material: Article
• Authors: John D Groot, University of California, San Francisco; Martina Ott, University of Texas MD Anderson Cancer Center; Jun Wei, University of Texas MD Anderson Cancer Center; Cynthia Kassab, University of Texas MD Anderson Cancer Center; Dexing Fang, University of Texas MD Anderson Cancer Center; Hinda Najem, Northwestern University Feinberg School of Medicine; Barbara O'Brien, University of Texas MD Anderson Cancer Center; Shiao-Pei Weathers, University of Texas MD Anderson Cancer Center; Carlos K Matsouka, University of Texas MD Anderson Cancer Center; Nazanin K Majd, University of Texas MD Anderson Cancer Center; Rebecca A Harrison, University of Texas MD Anderson Cancer Center; Gregory N Fuller, University of Texas MD Anderson Cancer Center; Jason T Huse, University of Texas MD Anderson Cancer Center; James P Long, University of Texas MD Anderson Cancer Center; Raymond Sawaya, University of Texas MD Anderson Cancer Center; Ganesh Rao, University of Texas MD Anderson Cancer Center; Tobey MacDonald, Emory University; Waldemar Priebe, University of Texas MD Anderson Cancer Center; Michael Decuypere, Northwestern University Feinberg School of Medicine; Amy B Heimberger, Northwestern University Feinberg School of Medicine
• Language: English
• Date: 2022-06-01
• Publisher: Future Medicine Ltd
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.2217/cns-2022-0005
• Title of Journal or Parent Work: CNS Oncology
• Volume: 11
• Issue: 2
• Start Page: CNS87
• End Page: CNS87
• Grant/Funding Information: Study supported by NIH grants: CA120813, NS120547, CA093459 and Cancer Prevention Research Institute of Texas (CPRIT) IIRA RP160482.; Support for this research was received from The Ben and Catherine Ivy Foundation and The University of Texas MD Anderson Moon Shot Program.
• Keywords: glioblastoma; Tyrphostins; Phase I; Glioma; Glioblastoma; toxicity; Humans; STAT3 Transcription Factor; STAT3 inhibitor; Pyridines; Brain Neoplasms; Disease Progression
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Aim: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods: In a first-in-human open-label, single-center, single-Arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2 was 2-3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.