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

John de Groot, Martina Ott, Jun Wei, Cynthia Kassab, Dexing Fang, Hinda Najem, Barbara O'Brien, Shiao-Pei Weathers, Carlos Kamiya Matsouka, Nazanin K Majd, Rebecca A Harrison, Gregory N Fuller, Jason T Huse, James P Long, Raymond Sawaya, Ganesh Rao, Tobey J MacDonald, Waldemar Priebe, Michael DeCuypere, Amy B Heimberger, John de Groot, Martina Ott, Jun Wei, Cynthia Kassab, Dexing Fang, Hinda Najem, Barbara O'Brien, Shiao-Pei Weathers, Carlos Kamiya Matsouka, Nazanin K Majd, Rebecca A Harrison, Gregory N Fuller, Jason T Huse, James P Long, Raymond Sawaya, Ganesh Rao, Tobey J MacDonald, Waldemar Priebe, Michael DeCuypere, Amy B Heimberger

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.

Trial registration: ClinicalTrials.gov NCT02977780.

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

Conflict of interest statement

Financial & competing interests disclosure

Support for this research was received from The Ben and Catherine Ivy Foundation and The University of Texas MD Anderson Moon Shot Program. Amy B Heimberger has licensed intellectual property to Celldex Therapeutics and DNAtrix. She serves on the advisory board of Caris Life Sciences, WCG Oncology, owns stock in Caris Life Sciences and has received research funding from Celularity Inc. and Codiak BioScience Inc. Moleculin has licensed WP1066 from MD Anderson Cancer Center that was created by Waldemar Priebe and provided study drug and reimbursement for PK analysis. Study supported by NIH grants: CA120813, NS120547, CA093459 and Cancer Prevention Research Institute of Texas (CPRIT) IIRA RP160482. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. Clinical outcome data of WP1066…
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…
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.

References

    1. Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987–996 (2005).
    1. Abou-Ghazal M, Yang DS, Qiao W et al. The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin. Cancer Res. 14(24), 8228–8235 (2008).
    1. Huang S. Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin. Cancer Res. 13(5), 1362–1366 (2007).
    1. Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat. Rev. Cancer 4(2), 97–105 (2004).
    1. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7(1), 41–51 (2007).
    1. Kong LY, Wei J, Sharma AK et al. A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells. Cancer Immunol. Immunother. 58(7), 1023–1032 (2009).
    1. Sherry MM, Reeves A, Wu JK, Cochran BH. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27(10), 2383–2392 (2009).
    1. Wei J, Barr J, Kong LY et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol. Cancer Ther. 9(1), 67–78 (2010).
    1. Wu A, Wei J, Kong LY et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro. Oncol. 12(11), 1113–1125 (2010).
    1. Madden T, Kazerooni R, Myer J et al. The preclinical pharmacology of WP1066, a potent small molecule inhibitor of the JAK2/STAT3 pathway. Cancer Res. 66(Suppl. 8), 1139–1140 (2006).
    1. Hussain SF, Kong LY, Jordan J et al. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 67(20), 9630–9636 (2007).
    1. Phi JH, Choi SA, Kim SK, Wang KC, Lee JY, Kim DG. overcoming chemoresistance of pediatric ependymoma by inhibition of STAT3 signaling. Transl. Oncol. 8(5), 376–386 (2015).
    1. Geng L, Li X, Zhou X, Fang X, Yuan D, Wang X. WP1066 exhibits antitumor efficacy in nasal-type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway. Oncol. Rep. 36(5), 2868–2874 (2016).
    1. Zhou X, Ren Y, Liu A et al. STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo. Oncol. Rep. 31(5), 2173–2180 (2014).
    1. Horiguchi A, Asano T, Kuroda K et al. STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. Br. J. Cancer 102(11), 1592–1599 (2010).
    1. Chiu HC, Chou DL, Huang CT et al. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochem. Pharmacol. 81(11), 1263–1270 (2011).
    1. Judd LM, Menheniott TR, Ling H et al. Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLOS ONE 9(5), e95993 (2014).
    1. Lee HT, Xue J, Chou PC et al. Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells. Oncotarget 6(12), 10016–10029 (2015).
    1. Kong LY, Wu AS, Doucette T et al. Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immunotherapeutic responses. Clin. Cancer Res. 16(23), 5722–5733 (2010).
    1. Kupferman ME, Jayakumar A, Zhou G et al. Therapeutic suppression of constitutive and inducible JAK\STAT activation in head and neck squamous cell carcinoma. J. Exp. Ther. Oncol. 8(2), 117–127 (2009).
    1. Zhou X, Ren Y, Liu A et al. STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo. Oncol. Rep. 31(5), 2173–2180 (2014).
    1. Hatiboglu MA, Kong LY, Wei J et al. The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models. Int. J. Cancer 131(1), 8–17 (2012).
    1. Kong LY, Abou-Ghazal MK, Wei J et al. A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells. Clin. Cancer Res. 14(18), 5759–5768 (2008).
    1. Kong LY, Gelbard A, Wei J et al. Inhibition of p-STAT3 enhances IFN-alpha efficacy against metastatic melanoma in a murine model. Clin. Cancer Res. 16(9), 2550–2561 (2010).
    1. Iwamaru A, Szymanski S, Iwado E et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26(17), 2435–2444 (2007).
    1. Kortylewski M, Kujawski M, Wang T et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med. 11(12), 1314–1321 (2005).
    1. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7(2), 27–31 (2016).
    1. Okada H, Weller M, Huang R et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16(15), e534–e542 (2015).
    1. Kleiveland CR. Peripheral blood mononuclear cells. In: The Impact of Food Bioactives on Health: in vitro and ex vivo models. Verhoeckx K, Cotter P, López-Expósito I (Eds). Springer, Switzerland: (2015).
    1. Humphries W, Wang Y, Qiao W et al. Detecting the percent of peripheral blood mononuclear cells displaying p-STAT-3 in malignant glioma patients. J. Transl. Med. 7, 92 (2009).
    1. Zorn E, Nelson EA, Mohseni M et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108(5), 1571–1579 (2006).
    1. Ott M, Kassab C, Marisetty A et al. Radiation with STAT3 blockade triggers dendritic cell-T cell interactions in the glioma microenvironment and therapeutic efficacy. Clin. Cancer Res. 26(18), 4983–4994 (2020).
    1. de Groot J, Liang J, Kong LY et al. Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma. Oncotarget 3(9), 1036–1048 (2012).
    1. Kohsaka S, Wang L, Yachi K et al. STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. Mol. Cancer Ther. 11(6), 1289–1299 (2012).
    1. Wang Y, Chen L, Bao Z et al. Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and beta-catenin signaling pathways. Oncol. Rep. 26(5), 1173–1180 (2011).
    1. Yuan L, Zhang H, Liu J et al. STAT3 is required for Smo-dependent signaling and mediates Smo-targeted treatment resistance and tumorigenesis in Shh medulloblastoma. Mol. Oncol. 16(4), 1009–1025 (2022).
    1. Metrock LK, Liu J, Liangping Y, Zhang H, Dey A, MacDonald T. Abstract 3196: STAT3 inhibitor WP1066 as a novel therapeutic for medulloblastoma. Cancer Res. 76(Suppl. 14), 3196–3196 (2016).
    1. Louis DN, Perry A, Wesseling P et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro. Oncol. 23(8), 1231–1251 (2021).
    1. Zarnett OJ, Sahgal A, Gosio J et al. Treatment of elderly patients with glioblastoma: a systematic evidence-based analysis. JAMA Neurol. 72(5), 589–596 (2015).
    1. Hegi ME, Genbrugge E, Gorlia T et al. MGMT Promoter Methylation cut-off with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide: A Pooled Analysis of Four Clinical Trials. Clin. Cancer Res. 25(6), 1809–1816 (2019).
    1. Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352(10), 997–1003 (2005).

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