A phase Ib trial of ERK inhibition with ulixertinib combined with palbociclib in patients (Pts) with advanced solid tumors.

Abstract

3103 Background: Activating KRAS mutations are the most frequently detected aberrant oncogenes in pancreatic adenocarcinoma. Combination strategies to target the downstream RAF-MEK-ERK effector pathway are a rational approach. Preclinical data with ERK and CDK4/6 inhibition in both pancreatic cancer cell lines and xenografts demonstrates synergistic cell death and tumor growth suppression. Ulixertinib (BVD-523) is an oral small molecule inhibitor of ERK1/2. This phase 1b study evaluated the safety, pharmacokinetics, and early clinical efficacy of ulixertinib when combined with the oral CDK4/6 inhibitor palbociclib in pts with advanced solid tumors. Methods: Using a 3+3 design, pts received ulixertinib at a starting dose of 300mg (range 300-600mg) twice daily continuously with palbociclib at a starting dose of 75mg (range 75-125mg) on D1-21 out of a 28 day cycle. The primary objective was to establish the maximum tolerated dose (MTD) of the combination. Secondary objectives included characterizing safety and estimating progression free survival (PFS). Dose limiting toxicities (DLTs) were evaluated during the first cycle of treatment. Adverse events were graded by CTCAE v4.03. Response was evaluated after 2 cycles (8 weeks) by RECIST 1.1 criteria. Results: 26 pts were enrolled (13 colorectal, 9 pancreas, 2 melanoma, 1 cholangiocarcinoma, 1 GIST); 16 were evaluable for response. The MTD of the combination was ulixertinib 450mg BID and palbociclib 125mg daily. DLTs included grade 3 fatigue, grade 3 acute kidney injury and grade 3 hyponatremia (Table). Due to toxicity in cohort 3, the protocol was amended to include two additional cohorts (2A and 2B) with a reduced dose of ulixertinib and increasing doses of palbociclib. The most common treatment-related adverse events (TRAEs) (all grades) were fatigue (70%), rash (62%) and nausea (54%). The most common laboratory TRAEs were decreased lymphocyte count (77%), decreased WBC count (73%) and anemia (65%). Grade 3 TRAEs were decreased WBC count, decreased lymphocyte count, anemia and fatigue. No grade 4/5 TRAEs were reported. Three pts demonstrated stable disease (SD). For this heavily pre-treated pt population, PFS was 2.05 months (95% CI 1.87, not determined). PK analysis for ulixertinib and palbociclib was linear and consistent with previously reported data; no drug-drug interactions were observed. Conclusions: The MTD of this phase Ib study of advanced solid tumor pts was ulixertinib 450mg BID combined with palbociclib 125 mg daily. At this dosing, 2 pts demonstrated SD, one with pancreatic cancer and one with cholangiocarcinoma. An expansion cohort of metastatic pancreatic cancer pts is ongoing. Clinical trial information: NCT03454035. [Table: see text]