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

doi:10.2217/cns-2022-0005

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^*

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

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.

Original language	English (US)
Article number	CNS87
Journal	CNS oncology
Volume	11
Issue number	2
DOIs	https://doi.org/10.2217/cns-2022-0005
State	Published - Jun 2022

Funding

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.

Keywords

Glioblastoma
Phase I
STAT3 inhibitor
Toxicity

ASJC Scopus subject areas

Neurology
Clinical Neurology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2217/cns-2022-0005

Cite this

Groot, J. D., Ott, M., Wei, J., Kassab, C., Fang, D., Najem, H., O'Brien, B., Weathers, S. P., Matsouka, C. K., Majd, N. K., Harrison, R. A., Fuller, G. N., Huse, J. T., Long, J. P., Sawaya, R., Rao, G., Macdonald, T. J., Priebe, W., Decuypere, M., & Heimberger, A. B. (2022). A first-in-human Phase i trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma. CNS oncology, 11(2), Article CNS87. https://doi.org/10.2217/cns-2022-0005

@article{9cc894fbbe7d4a22864353ac44d72b08,

title = "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 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.",

keywords = "Glioblastoma, Phase I, STAT3 inhibitor, Toxicity",

author = "Groot, {John De} and Martina Ott and Jun Wei and Cynthia Kassab and Dexing Fang and Hinda Najem and Barbara O'Brien and Weathers, {Shiao Pei} and Matsouka, {Carlos Kamiya} and Majd, {Nazanin K.} and Harrison, {Rebecca A.} and Fuller, {Gregory N.} and Huse, {Jason T.} and Long, {James P.} and Raymond Sawaya and Ganesh Rao and Macdonald, {Tobey J.} and Waldemar Priebe and Michael Decuypere and Heimberger, {Amy B.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

month = jun,

doi = "10.2217/cns-2022-0005",

language = "English (US)",

volume = "11",

journal = "CNS oncology",

issn = "2045-0907",

publisher = "Future Medicine Ltd.",

number = "2",

}

Groot, JD, Ott, M, Wei, J, Kassab, C, Fang, D, Najem, H, O'Brien, B, Weathers, SP, Matsouka, CK, Majd, NK, Harrison, RA, Fuller, GN, Huse, JT, Long, JP, Sawaya, R, Rao, G, Macdonald, TJ, Priebe, W, Decuypere, M & Heimberger, AB 2022, 'A first-in-human Phase i trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma', CNS oncology, vol. 11, no. 2, CNS87. https://doi.org/10.2217/cns-2022-0005

TY - JOUR

T1 - A first-in-human Phase i trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma

AU - Groot, John De

AU - Ott, Martina

AU - Wei, Jun

AU - Kassab, Cynthia

AU - Fang, Dexing

AU - Najem, Hinda

AU - O'Brien, Barbara

AU - Weathers, Shiao Pei

AU - Matsouka, Carlos Kamiya

AU - Majd, Nazanin K.

AU - Harrison, Rebecca A.

AU - Fuller, Gregory N.

AU - Huse, Jason T.

AU - Long, James P.

AU - Sawaya, Raymond

AU - Rao, Ganesh

AU - Macdonald, Tobey J.

AU - Priebe, Waldemar

AU - Decuypere, Michael

AU - Heimberger, Amy B.

PY - 2022/6

Y1 - 2022/6

N2 - 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.

AB - 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.

KW - Glioblastoma

KW - Phase I

KW - STAT3 inhibitor

KW - Toxicity

UR - http://www.scopus.com/inward/record.url?scp=85130997343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130997343&partnerID=8YFLogxK

U2 - 10.2217/cns-2022-0005

DO - 10.2217/cns-2022-0005

M3 - Article

C2 - 35575067

AN - SCOPUS:85130997343

SN - 2045-0907

VL - 11

JO - CNS oncology

JF - CNS oncology

IS - 2

M1 - CNS87

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Supplementary Tables 1 and 2. A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma.

Cite this

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Datasets

Supplementary Tables 1 and 2. A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma.

Cite this