A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies

Authors

• Sarina A Piha-Paul, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Ecaterina E Dumbrava, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Binoj C Nair, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Wendy Xiong, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Li Xu, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Rosa Mostorino, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Vivek Subbiah, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Nizar Tannir, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States
• Siqing Fu, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Aung Naing, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Filip Janku, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Daniel D Karp, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Shreyaskumar Patel, Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States
• Najat C Daw, Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States
• David Hong, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States
• Funda Meric-Bernstam, Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, United States; Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, United States; The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, United States
• Ralph G. Zinner, Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, United StatesFollow

Document Type

Article

Publication Date

5-7-2021

Comments

This article is the author's final published version in OncoTargets and Therapy, Volume 14, pp. 3037-3049.

OncoTargets and Therapy, published by Dove Medical Press, is acknowledged as the article's original place of publication.

The published version is available at https://doi.org/10.2147/OTT.S291801

Copyright © 2021 Piha-Paul et al.

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).

Abstract

Background: Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib.

Methods: We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib.

Results: Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR).

Conclusion: Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.

Recommended Citation

Piha-Paul, Sarina A; Dumbrava, Ecaterina E; Nair, Binoj C; Xiong, Wendy; Xu, Li; Mostorino, Rosa; Subbiah, Vivek; Tannir, Nizar; Fu, Siqing; Naing, Aung; Janku, Filip; Karp, Daniel D; Patel, Shreyaskumar; Daw, Najat C; Hong, David; Meric-Bernstam, Funda; and Zinner, Ralph G., "A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies" (2021). Department of Medical Oncology Faculty Papers. Paper 141.
https://jdc.jefferson.edu/medoncfp/141

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License

PubMed ID

33994796

Language

English