First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors

Abstract

Purpose: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766.Experimental Design: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)].Results: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C max occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma.Conclusion: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.

Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations

“…Recently, the MEK inhibitor trametinib has been shown to improve overall survival in BRAF V600-mutated metastatic melanoma (8) compared with dacarbazine or paclitaxel chemotherapy and has been approved by the Food and Drug Administration. Other small-molecule inhibitors of MEK are currently under clinical investigation (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). RO4987655 is a potent, highly selective adenosine triphosphate noncompetitive oral MEK inhibitor with manageable toxicity profile, favorable pharmacokinetics/pharmacodynamics characteristics, and preliminary antitumor activity in a phase I dose escalation (part 1) study in advanced solid cancers (21).…”

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

“…The toxicity profile of WX-554 had similarities to that of other MEK inhibitors, with fatigue, diarrhoea, and dermatological reactions being the most frequent adverse reactions [13][14][15][16][17][18].…”

“…The mean half-life of 28 hours of WX-554 is longer than that of most MEK inhibitors currently undergoing clinical investigations, with the exception of trametinib [15] and the dual RAF/MEK inhibitor RO5126766 [18]. This long half-life permitted the investigation of both weekly and then twice weekly dosing schedules.…”

Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

“…RO5126766 is a first-in-class, selective dual BRAF/CRAF and MEK inhibitor currently in early development for advanced solid tumors (55). Studies in tumor cell lines suggest that RO5126766 may be a good candidate for targeting RAS-mutated tumor cells (56).…”

“…Tumor shrinkage was observed in approximately 40% of patients across all tumor types, with 3 PRs [all in patients with BRAF-(n ¼ 2) or NRAS-(n ¼ 1) mutant melanoma; ref. 55)]. Seventeen of 39 analyzed tumors contained mutations in BRAF, NRAS/HRAS, or PI3KCA; 1 patient showed loss of PTEN staining, while PTEN was intact in the 3 patients who achieved a PR, indicating PTEN suppression of PI3K/AKT pathway activation.…”