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Clinical Trial
. 2018 Feb 22;3(4):e92352.
doi: 10.1172/jci.insight.92352.

Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

Stergios J Moschos  1 , Ryan J Sullivan  2 , Wen-Jen Hwu  3 , Ramesh K Ramanathan  4 , Alex A Adjei  5 , Peter C Fong  6 , Ronnie Shapira-Frommer  7 , Hussein A Tawbi  8 , Joseph Rubino  9 , Thomas S Rush 3rd  9 , Da Zhang  9 , Nathan R Miselis  9 , Ahmed A Samatar  9 , Patrick Chun  9 , Eric H Rubin  9 , James Schiller  9 , Brian J Long  9 , Priya Dayananth  9 , Donna Carr  9 , Paul Kirschmeier  9 , W Robert Bishop  9 , Yongqi Deng  9 , Alan Cooper  9 , Gerald W Shipps  9 , Blanca Homet Moreno  10 , Lidia Robert  10 , Antoni Ribas  10 , Keith T Flaherty  2
Affiliations
Clinical Trial

Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

Stergios J Moschos et al. JCI Insight. .

Abstract

Background: Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. VSports手机版.

Methods: We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. V体育安卓版.

Results: MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts V体育ios版. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. .

Conclusion: MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. VSports最新版本.

Trial registration: ClinicalTrials V体育平台登录. gov NCT01358331. .

Funding: Merck Sharp & Dohme Corp. , a subsidiary of Merck & Co. Inc. , and NIH (P01 CA168585 and R35 CA197633) VSports注册入口. .

Keywords: Cancer; Clinical Trials; Melanoma; Oncology; Signal transduction. V体育官网入口.

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Figures

Figure 1
Figure 1. Structure and biochemical activity of MK-8353 in vitro and in vivo.
(A) Chemical structure of MK-8353. (B) MK-8353 inhibits ERK and RSK phosphorylation. A2058 cells (1 × 106 cells per 10-cm dish) were treated with increasing concentrations of MK-8353 (nM) for 24 hours. Whole cell lysates were subjected to immunoblot analysis using antibodies described in the Methods section. Image shows a representative immunoblot of a total of two experiments. (C and D) MK-8353 (30–60 mpk) inhibits ERK phosphorylation in Colo-205 human colon cancer tumor xenograft tissues (C) and paired normal skin tissues (D) as early as 1 hour following a single dose of MK-8353 versus drug vehicle (V). Xenograft tumors and same animal normal skin tissue were harvested (3 mice per group), and homogenates from excised tissues were subjected to immunoblot analysis using antibodies against phosphorylated/activated ERK (pERK) and total ERK (tERK). Experiment in each tumor xenograft was performed once. See complete unedited blots in the supplemental material.
Figure 2
Figure 2. MK-8353 induces tumor growth inhibition or regression across various human cancer xenograft models.
Female athymic nude mice (Colo-205) or SCID mice (SK-MEL-28) were injected with human Colo-205 colon cancer cells (B) and SK-MEL-28 melanoma cells (A) (both BRAFV600E-mutant), as described in the Methods section. (A and B). Tumor growth curves show mean tumor volumes ± SEM (10 mice per group for each xenograft experiment). There was a statistically significant dose-dependent effect on tumor growth compared with the vehicle-treated group in both xenograft models that ranged from tumor growth inhibition (TGI) to regression (REG) and was present as early as day 3 from treatment initiation (P < 0.01, across all time points except for the day 3 time point in the Colo-205 xenograft model, in which the 30-mpk group was significantly different, P < 0.05; Student’s t test). (C and D) Expression of pERK by tissue immunohistochemistry in Colo-205 tumor xenografts (C) and same-animal normal skin tissues (D) following a single dose of MK-8353 administered by oral gavage at various doses. Representative tissue sections from corresponding tissues that were harvested at various time points (0–12 hours) following a single dose of MK-8353 were stained with antibodies against pERK. See the Methods section for details and Supplemental Figure 1 for representative images of 3 animals, with tumors and normal skin imaged at each time point. Results are shown as percentage change of pERK from vehicle using the formula described in the Methods section. mpk, milligrams per kilogram; TGI, tumor growth inhibition; REG; regression; Veh, drug vehicle.
Figure 3
Figure 3. CONSORT diagram of the MK-8353-001 clinical trial.
The flow chart shows the number of patients who were enrolled in parts 1a and 1b, received at least 1 dose of MK-8353, developed dose-limiting toxicity (DLT), and were evaluable for antitumor response by RECIST v1.1 criteria.
Figure 4
Figure 4. Mean plasma concentration-time profiles (semi-log scale) of MK-8353 in the MK-8353-001 study.
Figure 5
Figure 5. Effect of MK-8353 on pERK protein levels in normal epidermis in the MK-8353-001 study.
Patients with the baseline (red bar) and at least 1 on-treatment biopsy (day 8, green bar; day 15, gray bar) are shown. Corrective pERK levels (H-score mean ± SD) are shown. Asterisks show significant differences compared with baseline (*P < 0.05, 1-way ANOVA). Stable disease (SD) is shown in blue font; partial response (PR) is shown in red font. All other patients were nonevaluable for the efficacy endpoint. Scale bar: 200 μm.
Figure 6
Figure 6. Investigators’ assessment of objective tumor responses in evaluable patients (n = 15) in the MK-8353-001 study.
With the exception of subjects 1004, 2002, 2013, and 2004, whose tumor assessments were performed prior to completion of 2 cycles (*), as well as subjects 2011 and 2008, whose best antitumor response occurred after 4 cycles (**), tumor assessments were completed following completion of 2 cycles. Three patients achieved partial response (PR).
See this image and copyright information in PMC

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