First results of migoprotafib, a potent and highly selective Src homology-2 domain-containing phosphatase 2 (SHP2) inhibitor in patients with advanced solid tumors.

IF 5.3 2区 医学 Q1 ONCOLOGY
Melissa L Johnson, Beni B Wolf, Judy S Wang, Alexander Philipovskiy, Geoffrey I Shapiro, Bruno Bockorny, Wei Guo, Jinshan Shen, Kai Yu Jen, MaryBeth LeRose, Tamieka Lauz Hunter, Mahesh Padval, Oleg Schmidt-Kittler, Namrata Bhatia, Sarita Dubey, Julia Suchomel, Johanna C Bendell, Shekeab Jauhari, Jennifer Eng-Wong, Jessica J Lin
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引用次数: 0

Abstract

Src homology-2 domain-containing phosphatase 2 (SHP2) promotes RAS-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective SHP2 inhibitor designed for the treatment of RAS-MAPK driven cancers, particularly in combination with other targeted agents. Here we report first-in-human study results of single agent migoprotafib in advanced solid tumor patients. We conducted a phase 1a, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics, pharmacodynamics (peripheral blood pERK) and preliminary anti-tumor activity. Fifty-six heavily pre-treated patients were treated with migoprotafib (10-150 mg QD). Migoprotafib had a rapid absorption rate (~0.5-2 hours) with dose-dependent increases in exposure and pathway modulation (pERK changes). The maximum tolerated dose was 100 mg and the recommended phase 2 dose (RP2D) was 60 mg daily (QD) based on safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, AST increase and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports QD dosing and demonstrated promising safety, tolerability, and clinical activity at the RP2D. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.

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来源期刊
CiteScore
11.20
自引率
1.80%
发文量
331
审稿时长
3 months
期刊介绍: Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
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