On July 9, 2020 JS InnoPharm Ltd reported the enrollment of the first patient in a Phase 1, open-label, monotherapy dose-escalation and expansion study of JSI-1187, the company’s lead investigational drug candidate targeting the enzymes ERK1 and ERK2 (Press release, JS InnoPharm, JUL 9, 2020, View Source [SID1234561801]). The study is being conducted at 4 NCI-designated Comprehensive Cancer Centers in the U.S. JS InnoPharm holds the U.S. IND for JSI-1187, and this trial is being managed by Strategia Pharmaceuticals LLC, JS InnoPharm’s clinical development partner in the United States. Initiation of this clinical trial represents an important step in the company’s efforts to discover and develop precision medicine for cancer patients.
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of JSI-1187 in patients with relapsed, refractory solid tumors with MAPK mutations. The study will comprise three components: (1) a dose escalation phase of JSI-1187 monotherapy for patients with solid tumors, (2) a dose escalation phase of JSI-1187 in combination with BRAF inhibitor, dabrafenib, and (3) an expansion phase for patients with tumors harboring specific mutations.
"JSI-1187 is a selective ERK1/2 inhibitor. By utilizing an ERK inhibitor against tumors harboring mutations in the MAPK pathway, we hope to develop more effective single-agent and combination therapies by preventing the early development of resistance seen with current MAPK targeted agents," said Dr. Linda Paradiso, Chief Development Officer for Strategia Pharmaceuticals.
The Role of ERK in Cancer
MAPK signaling via the RAS-RAF-MEK-ERK cascade plays a critical role in cancer growth and proliferation. Alterations in the MAPK/ERK pathway are found in a variety of cancer types, with KRAS mutations in pancreatic (>90%), biliary tract (3-50%), colorectal (30-50%), lung (25-30%), ovarian (15-39%) and endometrial (18%) cancers; NRAS mutations in 20% of melanoma; and BRAF V600 mutations in 50% of melanoma and 7% of a variety of other tumor types. Although it has been demonstrated that BRAF/MEK inhibitor-targeted combination therapy provides a significant benefit beyond single agent therapy in melanoma and other cancers, the majority of patients eventually develop resistance and disease progression. Several mechanisms of acquired resistance have been identified and central to these mechanisms is the reactivation of ERK signaling. Therefore, ERK inhibition may provide the opportunity to avoid or overcome resistance from upstream mechanisms, as it is the most distal kinase of this signaling pathway.
About JSI-1187
JSI-1187 is a selective and orally administered small molecule inhibitor of ERK1 and ERK2. In preclinical studies, it demonstrated high potency against a variety of tumors with MAPK pathway mutations.