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Clinical Trial
. 2019 Sep 15;25(18):5475-5484.
doi: 10.1158/1078-0432.CCR-18-1881. Epub 2019 Jun 11.

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

Razelle Kurzrock #  1 , Douglas W Ball #  2   3 , Marianna L Zahurak  2 , Barry D Nelkin  2 , Vivek Subbiah  1 , Shabina Ahmed  3 , Ashley O'Connor  2 , Enusha Karunsena  2 , Rose M Parkinson  2 , Justin A Bishop  4 , Yoonji Ha  2 , Rajni Sharma  4 , Christopher D Gocke  2 , Ralph Zinner  1 , Michelle A Rudek  2 , Steven I Sherman #  1 , Nilofer S Azad #  5
Affiliations
Clinical Trial

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

Razelle Kurzrock et al. Clin Cancer Res. .

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.

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Figures

Figure 1.:
Figure 1.:
Best RECIST 1.1 criteria responses in dose escalation cohort. Twenty-five patients were available for response (24 patients represented in figure and patient 25 not represented because of clinical progression without imaging). Abbreviations: BCC, basal cell; CCA, cholangiocarcinoma, CRC, colorectal; EC, endometrial, FTC, follicular thyroid, MM, melanoma; MSC, maxillary sinus; OV, ovarian; PANC, pancreatic islet cell; PSC, papillary thyroid; SSC, squamous cell tongue; SS, synovial cell carcinoma; THY, thyroid; ULS, uterine leiomyosarcoma.
Figure 2.:
Figure 2.:
Best RECIST 1.1 criteria responses in differentiated thyroid cohort. Eleven patients are represented in the figure, with the 12th evaluable patient not represented because of clinical progression without imaging. * Represents new lesions resulting in RECIST criteria progression.
Figure 3.:
Figure 3.:
Kaplan–Meier estimate of PFS (A) and OS (B) in differentiated thyroid cohort. The dotted lines represent 95% CIs.
Figure 4.:
Figure 4.:
Change in pERK in relation to change in tumor size. Pre- versus posttreatment biopsies were assessed for pERK. Changes in tumor size were assessed by RECIST 1.1 criteria.
See this image and copyright information in PMC

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