A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies

Sarina A. Piha-Paul; Ecaterina E. Dumbrava; Binoj C. Nair; Wendy Xiong; Li Xu; Rosa Mostorino; Vivek Subbiah; Nizar Tannir; Siqing Fu; Aung Naing; Filip Janku; Daniel D. Karp; Shreyaskumar Patel; Najat C. Daw; David Hong; Funda Meric-Bernstam; Ralph Zinner

doi:10.2147/OTT.S291801

A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies

Sarina A. Piha-Paul
, Ecaterina E. Dumbrava
, Binoj C. Nair
, Wendy Xiong
, Li Xu
, Rosa Mostorino
, Vivek Subbiah
, Nizar Tannir
, Siqing Fu
, Aung Naing
, Filip Janku
, Daniel D. Karp
, Shreyaskumar Patel
, Najat C. Daw
, David Hong
, Funda Meric-Bernstam
, Ralph Zinner

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Pages (from-to)	3037-3049
Number of pages	13
Journal	OncoTargets and Therapy
Volume	14
DOIs	https://doi.org/10.2147/OTT.S291801
State	Published - 2021

Bibliographical note

Publisher Copyright:
© 2021 Piha-Paul et al.

Funding

from Jazz Pharmaceuticals, personal fees from PureT ech Health, Bio-Rad, Biocartis, outside the submitted work. Dr Shreyaskumar Patel reports personal fees from DAiichi SAnkyo, personal fees from Deciphera, consultant fees from Epizyme, Dova and Bayer , grants from Blueprint Medicines, Clinical T rial fees from Hutchison Medipharma, outside the submitted work. Dr David Hong reports grants from AbbV ie, grants, Grant/Research Support & Consulting/Advisory Role from Adaptimmune, grants from Aldi-Norte, grants, Grant/ Research Support & Consulting/Advisory Role from Amgen, grants from Astra-Zeneca, grants, Grant/Research Support, Consulting/Advisory Role, T ravel, Accommodations, Expenses from Bayer , grants from BMS, grants from Daiichi-Sankyo, grants from Eisai, grants from Fate Therapeutics, grants, Grant/Research Support & Consulting/Advisory Role from Genentech, grants from Genmab, grants from Ignyta, grants, Grant/Research Support & Consulting/Advisory Role from Infinity , grants from Kite, grants from Kyowa, grants from Lily , grants, Grant/Research Support & T ravel, Accommodations, Expenses from LOXO, grants from Merck, grants from MedImmune, grants from Mirati, grants, Grant/Research Support & T ravel, Accommodations, Expenses from miRNA, grants from Molecular T emplates, grants from Mologen, grants from NCI-CTEP , grants from Novartis, grants, Grant/Research Support & Consulting/Advisory Role from Numab, grants, Grant/Research Support & Consulting/Advisory Role from Pfizer , grants, Grant/ Research Support & Consulting/Advisory Role from Seattle Genetics, Grant/Research Support & Consulting/ Advisory Role from T akeda, grants from T urning Point Therapeutics, V erstatem, Consulting/Advisory Role from Alpha Insights, Acuta, Axion, Baxter , Boxer Capital, COG, ECOR1, Expert Connect, GLG, Group H, Guidepoint, H.C. W ainwright, Janssen, Merrimack, Medscape, NTRK Connect, Prime Oncology , Slingshot, T rieza Therapeutics, W ebMD, T ravel, Accommodations, Expenses from ASCO, AACR, SITC, Advisor from Molecular Match, Founder from OncoResponse, Advisor from Presagia, outside the submitted work. Dr Funda Meric-Bernstam reports personal fees from Aduro BioT ech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F . Hoffman-La Roche Ltd., Genentech Inc., IBM W atson, Jackson Laboratory , Kolon Life Science, OrigiMed, P ACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., T yra Biosciences, Xencor , Zymeworks, Immunomedics, Advisory Committee from Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Silverback Therapeutics, Spectrum Pharmaceuticals Zentalis, grants from Aileron Therapeutics, Sponsored Research from AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals, Novartis, Puma Biotechnology Inc., T aiho Pharmaceutical Co., personal fees from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey , Beth Israel Deaconess Medical Center , outside the submitted work. The authors report no other conflicts of interest in this work. Dr Sarina A. Piha-Paul reports Clinical T rial Research Support (Received through the institution) from AbbV ie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sankyo, Inc., Eli Lilly , ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, Glaxo SmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., MedImmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer , Principia Biopharma, Inc., Puma Biotechnology , Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, T aiho Oncology , T esaro, Inc., T ransThera Bio, Core Grant (CCSG Shared Resources Clinical T rial Research Support (Received through the institution)) from NCI/NIH P30CA016672, outside the submitted work. Dr V ivek Subbiah reports Research funding/Grant support for clinical trials (to institution): Novartis, Bayer , Berghealth, Incyte, Fujifilm, Pharmamar , D3, Pfizer , Multivir , Amgen, AbbV ie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology , MedImmune, Altum, Dragonfly Therapeutics, T akeda, and National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center , T urning point therapeutics, Boston Pharmaceuticals. T ravel funding: Novartis, Pharmamar , ASCO, ESMO, Helsinn, Incyte, Ad Hoc Advisory Board: Helsinn, LOXO Oncology/Eli Lilly , R-Pharma US, INCYTE, QED pharma, MedImmune, Novartis, Signant Health. Dr Aung Naing reports grants from National Cancer Institute, grants from EMD Serono, grants from MedImmune, grants, non-financial support from ARMO BioSciences, grants from Karyopharm Therapeutics, grants from Incyte, grants, personal fees from Novartis, grants from Regeneron, grants from Merck, grants from Bristol-Myers Squibb, grants from Pfizer , grants, personal fees from CytomX Therapeutics, grants from Neon Therapeutics, grants from Calithera Biosciences, grants from T opAlliance Biosciences, grants from Eli Lilly , grants, personal fees from Kymab, grants from PsiOxus, grants from Arcus Biosciences, grants from NeoImmuneT ech, grants from ImmuneOncia, grants from Surface Oncology , grants, personal fees from Genome & Company , grants from OncoSec KEYNOTE-695, grants from STCube Pharmaceuticals, outside the submitted work; and Spouse • Research funding: Immune Deficiency Foundation, Jeffrey Modell Foundation and chao physician-scientist, and Baxalta. • Advisory board: T akeda, CSL, Behring, Horizon, and Pharming. Dr Filip Janku reports grants from Agios, grants, personal fees from Asana, grants from Astellas, grants from Astex, grants from Bayer , grants from Bicara, grants from BioMed V alley Discoveries, grants from Bioxcel, grants from Bristol-Myers Squibb, grants, personal fees from Deciphera, grants from FujiFilm Pharma, grants from Genentech, personal fees from Ideaya, grants from JS Innopharm, grants from Lilly , grants from Merck, grants, personal fees from Novartis, grants from Novellus, grants from Plexxikon, grants from Proximagen, grants from Sanofi, grants, personal fees from Sotio, grants from SpringBank Pharmaceuticals, grants from SQZ Biotechnologies, grants, personal fees from Synlogic, grants from Synthorx, grants from Symphogen, personal fees from Bausch Health, personal fees, Ownership Interests from Cardiff Oncology , personal fees from Guardant Health, personal fees from IFM Therapeutics, personal fees from Immunomet, personal fees from Illumina, personal fees

Funders	Funder number
ARMO BioSciences
AbbV ie, Inc.
Aileron Therapeutics Inc
Aminex Therapeutics
Amphivena Therapeutics, Inc.
Bayer Healthcare Pharmaceutical
BioMed V alley Discoveries
Calithera Biosciences	KEYNOTE-695
Calithera Biosciences Inc.
Cardiff Oncology
Chugai Pharmaceutical Co., Ltd., Curis, Inc.
Curis, Inc.
CytomX Therapeutics
CytomX Therapeutics Inc
Debiopharm International
Fate Therapeutics
FujiFilm Pharma
Guardant Health Inc.
Jacobio Pharmaceuticals Co., Ltd.
NCI-CTEP
Pieris Pharmaceuticals, Inc.
Principia Biopharma, Inc.
Puma Biotechnology Inc.
SQZ Biotechnologies
Samsung Bioepis
Seattle Genetics Inc., T yra Biosciences
SpringBank Pharmaceuticals
Synthorx
T rieza Therapeutics
eFFECTOR Therapeutics
National Institutes of Health (NIH)	P30CA016672
American Association for Cancer Research
National Childhood Cancer Registry – National Cancer Institute
Mayo Clinic Rochester
Jeffrey Modell Foundation
Bristol-Myers Squibb
Immune Deficiency Foundation
Eli Lilly and Company
International Business Machines Corporation
Pfizer
Astellas Pharma Inc.
AstraZeneca
Genentech Incorporated
Merck
Novartis
EMD Serono Research Institute
American Society of Clinical Oncology
Karyopharm Therapeutics
Novartis Pharmaceuticals Corporation
Boehringer-Ingelheim
Astex Pharmaceuticals
LAM Therapeutics
Neos Therapeutics
Bayer Fund
Daiichi Sankyo Company, Limited
Eisai
MedImmune

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ALK/ROS1
Crizotinib
MET
Pazopanib
VEGF

ASJC Scopus subject areas

Oncology
Pharmacology (medical)

Access to Document

10.2147/OTT.S291801

Cite this

Piha-Paul, S. A., Dumbrava, E. E., Nair, B. C., Xiong, W., Xu, L., Mostorino, R., Subbiah, V., Tannir, N., Fu, S., Naing, A., Janku, F., Karp, D. D., Patel, S., Daw, N. C., Hong, D., Meric-Bernstam, F., & Zinner, R. (2021). A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies. OncoTargets and Therapy, 14, 3037-3049. https://doi.org/10.2147/OTT.S291801

@article{2830e39a1dc44025a58a32499a30f5bf,

title = "A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies",

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.",

keywords = "ALK/ROS1, Crizotinib, MET, Pazopanib, VEGF",

author = "Piha-Paul, \{Sarina A.\} and Dumbrava, \{Ecaterina E.\} and Nair, \{Binoj C.\} and Wendy Xiong and Li Xu and Rosa Mostorino and Vivek Subbiah and Nizar Tannir and Siqing Fu and Aung Naing and Filip Janku and Karp, \{Daniel D.\} and Shreyaskumar Patel and Daw, \{Najat C.\} and David Hong and Funda Meric-Bernstam and Ralph Zinner",

note = "Publisher Copyright: {\textcopyright} 2021 Piha-Paul et al.",

year = "2021",

doi = "10.2147/OTT.S291801",

language = "English",

volume = "14",

pages = "3037--3049",

}

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 2021, 'A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies', OncoTargets and Therapy, vol. 14, pp. 3037-3049. https://doi.org/10.2147/OTT.S291801

TY - JOUR

T1 - A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies

AU - Piha-Paul, Sarina A.

AU - Dumbrava, Ecaterina E.

AU - Nair, Binoj C.

AU - Xiong, Wendy

AU - Xu, Li

AU - Mostorino, Rosa

AU - Subbiah, Vivek

AU - Tannir, Nizar

AU - Fu, Siqing

AU - Naing, Aung

AU - Janku, Filip

AU - Karp, Daniel D.

AU - Patel, Shreyaskumar

AU - Daw, Najat C.

AU - Hong, David

AU - Meric-Bernstam, Funda

AU - Zinner, Ralph

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - ALK/ROS1

KW - Crizotinib

KW - MET

KW - Pazopanib

KW - VEGF

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UR - https://www.scopus.com/pages/publications/85106160744#tab=citedBy

U2 - 10.2147/OTT.S291801

DO - 10.2147/OTT.S291801

M3 - Article

AN - SCOPUS:85106160744

SN - 1178-6930

VL - 14

SP - 3037

EP - 3049

JO - OncoTargets and Therapy

JF - OncoTargets and Therapy

ER -

A phase i trial of the met/alk/ros1 inhibitor crizotinib combined with the vegf inhibitor pazopanib in patients with advanced solid malignancies

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

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