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, Douglas W Ball, Marianna L. Zahurak, Barry D Nelkin, Vivek Subbiah, Shabina Ahmed, Ashley O'Connor, Enusha Karunsena, Rose Parkinson, Justin A. Bishop, Yoonji Ha, Rajni Sharma, Christopher Gocke, Ralph Zinner, Michelle Rudek-Renaut, Steven I. Sherman, Nilofer Azad

Research output: Contribution to journalArticle

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 r = -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.

Original languageEnglish (US)
Pages (from-to)5475-5484
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2019

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Vascular Endothelial Growth Factor Receptor
Mitogen-Activated Protein Kinase Kinases
Thyroid Neoplasms
Protein-Tyrosine Kinases
Neoplasms
Fatigue
Muscle Weakness
Transaminases
Vascular Endothelial Growth Factor A
Multicenter Studies
Disease-Free Survival
Diarrhea
pazopanib
trametinib
Confidence Intervals
Hypertension
Safety
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Kurzrock, Razelle; Ball, Douglas W; Zahurak, Marianna L.; Nelkin, Barry D; Subbiah, Vivek; Ahmed, Shabina; O'Connor, Ashley; Karunsena, Enusha; Parkinson, Rose; Bishop, Justin A.; Ha, Yoonji; Sharma, Rajni; Gocke, Christopher; Zinner, Ralph; Rudek-Renaut, Michelle; Sherman, Steven I.; Azad, Nilofer.

In: Clinical Cancer Research, Vol. 25, No. 18, 15.09.2019, p. 5475-5484.

Research output: Contribution to journalArticle

Kurzrock, Razelle ; Ball, Douglas W ; Zahurak, Marianna L. ; Nelkin, Barry D ; Subbiah, Vivek ; Ahmed, Shabina ; O'Connor, Ashley ; Karunsena, Enusha ; Parkinson, Rose ; Bishop, Justin A. ; Ha, Yoonji ; Sharma, Rajni ; Gocke, Christopher ; Zinner, Ralph ; Rudek-Renaut, Michelle ; Sherman, Steven I. ; Azad, Nilofer. / 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. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 18. pp. 5475-5484.
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T1 - 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

AU - Kurzrock, Razelle

AU - Ball, Douglas W

AU - Zahurak, Marianna L.

AU - Nelkin, Barry D

AU - Subbiah, Vivek

AU - Ahmed, Shabina

AU - O'Connor, Ashley

AU - Karunsena, Enusha

AU - Parkinson, Rose

AU - Bishop, Justin A.

AU - Ha, Yoonji

AU - Sharma, Rajni

AU - Gocke, Christopher

AU - Zinner, Ralph

AU - Rudek-Renaut, Michelle

AU - Sherman, Steven I.

AU - Azad, Nilofer

PY - 2019/9/15

Y1 - 2019/9/15

N2 - 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 r = -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.

AB - 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 r = -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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