Faculty Collaboration Database

A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers. Clin Cancer Res 2019 Sep 15;25(18):5475-5484

Date

06/13/2019

Pubmed ID

31186313

Pubmed Central ID

PMC7038784

DOI

10.1158/1078-0432.CCR-18-1881

Scopus ID

2-s2.0-85068791268 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

PURPOSE: Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC.

PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400-800 mg and trametinib 1-2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment.

RESULTS: Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = -0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008).

CONCLUSIONS: Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.

Author List

Kurzrock R, Ball DW, Zahurak ML, Nelkin BD, Subbiah V, Ahmed S, O'Connor A, Karunsena E, Parkinson RM, Bishop JA, Ha Y, Sharma R, Gocke CD, Zinner R, Rudek MA, Sherman SI, Azad NS

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Female
Humans
Indazoles
Kaplan-Meier Estimate
Male
Middle Aged
Mutation
Protein Kinase Inhibitors
Pyridones
Pyrimidines
Pyrimidinones
Receptors, Vascular Endothelial Growth Factor
Sulfonamides
Thyroid Neoplasms
Treatment Outcome