# Phase2 trial of MEK162 & imatinib combined therapy in GIST, IND119794(09/20/2013)

> **NIH FDA R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $125,000

## Abstract

Project Description/Summary
Gastrointestinal stromal tumor (GIST) is a rare type of cancer that affects approximately 40,000 patients with
an annual incidence of 5,000 cases in the US. It arises from the “pacemaker” cells of the gastrointestinal tract
and is mainly characterized by activating mutations in KIT or PDGFRA receptor tyrosine kinases. Despite the
initial clinical success of imatinib that targets mutant KIT/PDGFRA, nearly all advanced GIST patients develop
imatinib-resistance and eventually die of their disease. It is critical to gain a better understanding of the
pathogenesis of GIST and to develop novel treatment strategies that are 1) more effective than first-line
imatinib therapy and 2) can delay and/or prevent imatinib-resistance.
ETV1, an ETS family transcription factor and a well-established oncogene in prostate cancer and melanoma,
has recently been discovered to play a critical role in GIST oncogenesis. ETV1 is highly expressed and is
required for growth and survival of GISTs. ETV1 is a master regulator of the ICC-GIST lineage and is required
for GIST tumor initiation and maintenance in vivo. ETV1 and mutant KIT form a positive feedback circuit in
GIST oncogenesis, where the ETV1 protein is stabilized by active MAP kinase signaling downstream of KIT
signaling and stabilized ETV1 in turn upregulates KIT expression. Hence, ETV1 represents a novel drug target.
We demonstrated that the combination of MEK162 and imatinib can durably inhibit ETV1 protein and lead to
enhanced apoptosis in GIST cells and complete responses of GIST tumors. These preclinical data led to an
investigator initiated “phase Ib/II study of MEK162 in combination with imatinib in patients with untreated
advanced GIST” to directly evaluate the safety and clinical efficacy of this novel combination therapy in
advanced GIST. The phase Ib portion of the study has been completed and has demonstrated the safety and
defined the recommended phase II doses of the combination therapy in GIST patients. The phase II study is
currently accruing and forms the basis of this proposal. The primary goal of the phase II study is to evaluate
the efficacy of the combination of MEK162 and imatinib by RECIST responses in untreated advanced GIST
patients. The phase II trial included secondary endpoints that evaluate the progression free survival, overall
survival and respectability rate. There are mandatory pre- and post-treatment biopsies and biopsies at disease
progression for correlative studies that explore the effect of the combination therapy in ETV1 target inhibition:
a) inhibition of the ETV1 protein level, and 2) inhibition of the ETV1-dependent transcriptome. Additionally, we
will examine the genetic tumor heterogeneity and genetic basis of resistance mechanisms to the combination
therapy from the plasma tumor-derived cell-free DNA and clinical samples obtained at disease progression.
We believe that targeting ETV1 by the combination treatment strategy represents a novel app...

## Key facts

- **NIH application ID:** 10246608
- **Project number:** 3R01FD005731-04S1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ping Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2020
- **Award amount:** $125,000
- **Award type:** 3
- **Project period:** 2017-09-25 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246608

## Citation

> US National Institutes of Health, RePORTER application 10246608, Phase2 trial of MEK162 & imatinib combined therapy in GIST, IND119794(09/20/2013) (3R01FD005731-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10246608. Licensed CC0.

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