OncoTargets and Therapy (May 2021)

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

  • Piha-Paul SA,
  • Dumbrava EE,
  • Nair BC,
  • Xiong W,
  • Xu L,
  • Mostorino R,
  • Subbiah V,
  • Tannir N,
  • Fu S,
  • Naing A,
  • Janku F,
  • Karp DD,
  • Patel S,
  • Daw NC,
  • Hong D,
  • Meric-Bernstam F,
  • Zinner R

Journal volume & issue
Vol. Volume 14
pp. 3037 – 3049

Abstract

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Sarina A Piha-Paul,1 Ecaterina E Dumbrava,1 Binoj C Nair,1 Wendy Xiong,1 Li Xu,1 Rosa Mostorino,1 Vivek Subbiah,1 Nizar Tannir,2 Siqing Fu,1 Aung Naing,1 Filip Janku,1 Daniel D Karp,1 Shreyaskumar Patel,3 Najat C Daw,4 David Hong,1 Funda Meric-Bernstam,1,5,6 Ralph Zinner7 1Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Department of Breast Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 6The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USACorrespondence: Sarina A Piha-PaulInvestigational Cancer Therapeutics, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 455, Houston, TX, 77030, USATel +1 713-563-1055Fax +1 713-792-3535Email [email protected]: 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.Keywords: crizotinib, pazopanib, VEGF, ALK/ROS1, MET

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