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

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 T_1/2 was 2-3 h with a dose dependent increase in the C_max. 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.

Trial registration: ClinicalTrials.gov NCT02977780.

Keywords: Phase I; STAT3 inhibitor; glioblastoma; toxicity.

Figure 1.. Clinical outcome data of WP1066 treated patients.

(A) PFS based on radiographic evidence of tumor progression based on the increase in the volume of gadolinium enhancement on magnetic resonance imaging and (B) OS from the time of tumor recurrence. OS: Overall survival; PFS: Progression free survival.

Figure 2.. Tumor characterization and pharmacokinetics demonstrating immune STAT3 inhibition.

(A) Representative image of the glioma microenvironment at the time of initial diagnosis demonstrating relative rare infiltration of CD3⁺ T cells and the (B) heterogeneity of p-STAT3 expression at 40× magnification (subject 1). Immunohistochemical (IHC) analysis was used to detect membrane expression of CD3 on T cells and nuclear expression of p-STAT3 in all subjects enrolled (n = 8). (C) Representative flow cytometry image showing the mean fluorescent intensity (MFI) of intracellular p-STAT3 in PBMCs relative to isotype controls at baseline before administration of WP1066 and at 172 h (subject 1). Positive p-STAT3 expression was defined based on the isotype controls. (D) The percentage of p-STAT3+ PBMCs were then quantified longitudinally by flow cytometry. The percentage of p-STAT3+ PBMCs were graphed for each enrolled subject over time (top panel) and based as a mean with SEM of the entire group at each time point on a scatter plot (bottom panel). There was a statistical difference after 172 h of dosing by paired t-test (p = 0.0219). Statistical significance was not yet reached at 4, 24 or 168 h. FSC-H: Forward scatter parameter H; PBMC: Peripheral blood mononuclear cell; PE: Phycoerythrin fluorophore.