An ongoing, collaborative clinical trial has been expanded to evaluate the investigational protein kinase C inhibitor IDE196 in combination with the multikinase inhibitor crizotinib (Xalkori) for patients with GNAQ- or GNA11-mutated solid tumors, including metastatic uveal melanoma , skin melanoma, lung cancer, and colorectal cancer.
An ongoing, collaborative clinical trial (NCT03947385) between IDEAYA Biosciences, Inc. and Pfizer has been expanded to evaluate the investigational protein kinase C (PKC) inhibitor IDE196 in combination with the cMET multikinase inhibitor crizotinib (Xalkori) for patients with GNAQ- or GNA11-–mutated solid tumors, including metastatic uveal melanoma (MUM), skin melanoma, lung cancer, and colorectal cancer (CRC), according to IDEAYA Biosciences.1
IDEAYA Biosciences, Inc. will sponsor the trial, while Pfizer, which has exclusive worldwide rights to crizotinib, will supply crizotinibthe TKI. Pfizer has exclusive worldwide rights to crizotinib. The IDE196/crizotinib arm of the trial is set to be initiated between late 2020 and early 2021.
“We are excited to expand our agreement with Pfizer to evaluate the clinical combination of IDE196 and crizotinib in MUM and other solid tumors with GNAQ or GNA11 mutations,” said Mick O'Quigley, vice president and head of development operations of IDEAYA Biosciences.
IDEAYA Biosciences, Inc. identified cMET expression or activation has been identified as a potential prognostic biomarker of IDE196 treatment in patients with MUMmetastatic uveal melanoma. Additionally, the PKC inhibitor was found to demonstrated preclinical synergistic activity with crizotinib in this patient population.2
“We are excited to expand our agreement with Pfizer to evaluate the clinical combination of IDE196 and crizotinib in MUM and other solid tumors with GNAQ or GNA11 mutations,” said Mick O'Quigley, vice president and head of development operations of IDEAYA Biosciences, Inc. in the press release.
Mark Lackner, PhD, senior vice president and head of biology and translation sciences at IDEAYA Biosciences, Inc, added, “Through our translational research we have identified cMET expression as a potential biomarker, and we are excited to explore this rational combination between IDE196 and crizotinib clinically,” said Mark Lackner, PhD, senior vice president and head of biology and translation sciences at IDEAYA Biosciences.”
The initial collaboration and supply agreement between IDEAYA Biosciences, Inc. and Pfizer induced an expansion of the phase 2 portion of the trial and formed a joint development committee (JDC) between the companies. The JDC means that the parties will make joint decisions and share data regarding the results of the clinical trial. The companies will enter into good faith negotiations should clinical data obtained from the trial be used to obtain regulatory approvals or label changes.2
The initial agreement included an ongoing study evaluating IDE-196 in combination with the MEK inhibitor binimetinib (Mektovi). Dosing for the IDE196/binimetinib portion of the study commenced in July 2020 for patients with metastatic uveal melanoma, according to the news release.3
Prior to this,Previously, IDE196 was evaluated as monotherapy in an ongoing, phase 1, dose-escalation basket trial (NCT02601378). Data from the study, which were presented during the 2019 AACR Annual Meeting, reported an overall response rate of 13% (95% CI, 4%-31%) and a disease control rate of 73% among 30 patients treated with IDE196.4
Moreover, 4 patients achieved a partial response (PR), while an additional 2 patients had unconfirmed PRs.
All patients had MUM metastatic uveal melanoma and were treated with 200 mg, 300 mg, or 400 mg of twice-daily IDE196 twice daily.
The According to a press release, the 400-mg dose, given (with as a one-weekly 200-mg, twice-daily run-in) was selected as the recommended phase 2 dose of IDE196.5 With this dose, patients observed an approximately 44% higher average steady state exposure of free IDE196 (area under the curvefree) and an approximate 40% higher trough concentration of IDE196 compared with the 300-mg, twice-daily dose.
As of May 2019, 5 patients remained on IDE196 for longer than 18 months and 3 were on for more than 2 years.
Regarding safety with IDE196, the most frequently observed dose-limiting toxicity was transient hypotension, which was well managed.
IDE196 continues is also to being evaluated as monotherapy in an ongoing GNAQ/GNA11 non-MUM basket trial, as well as in the combination trials with binimetinib and crizotinib.