A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas

M. Agulnik, R. L B Costa, M. Milhem, A. W. Rademaker, B. C. Prunder, D. Daniels, B. T. Rhodes, C. Humphreys, S. Abbinanti, L. Nye, R. Cehic, A. Polish, C. Vintilescu, T. McFarland, K. Skubitz, Steven Robinson, Scott Heitaka Okuno, B. A. Van Tine

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS.

Original languageEnglish (US)
Pages (from-to)121-127
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Sarcoma
Disease-Free Survival
Survival Rate
Vascular Endothelial Growth Factors
Confidence Intervals
Hypertension
Vascular Endothelial Growth Factor Receptor
Leiomyosarcoma
Protein-Tyrosine Kinases
Nausea
Fatigue
Disease Progression
tivozanib
Diarrhea
Safety
Survival
Therapeutics
Population
Neoplasms

Keywords

  • Phase II
  • Sarcoma
  • Tivozanib
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Agulnik, M., Costa, R. L. B., Milhem, M., Rademaker, A. W., Prunder, B. C., Daniels, D., ... Van Tine, B. A. (2017). A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. Annals of Oncology, 28(1), 121-127. https://doi.org/10.1093/annonc/mdw444

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. / Agulnik, M.; Costa, R. L B; Milhem, M.; Rademaker, A. W.; Prunder, B. C.; Daniels, D.; Rhodes, B. T.; Humphreys, C.; Abbinanti, S.; Nye, L.; Cehic, R.; Polish, A.; Vintilescu, C.; McFarland, T.; Skubitz, K.; Robinson, Steven; Okuno, Scott Heitaka; Van Tine, B. A.

In: Annals of Oncology, Vol. 28, No. 1, 01.01.2017, p. 121-127.

Research output: Contribution to journalArticle

Agulnik, M, Costa, RLB, Milhem, M, Rademaker, AW, Prunder, BC, Daniels, D, Rhodes, BT, Humphreys, C, Abbinanti, S, Nye, L, Cehic, R, Polish, A, Vintilescu, C, McFarland, T, Skubitz, K, Robinson, S, Okuno, SH & Van Tine, BA 2017, 'A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas', Annals of Oncology, vol. 28, no. 1, pp. 121-127. https://doi.org/10.1093/annonc/mdw444
Agulnik M, Costa RLB, Milhem M, Rademaker AW, Prunder BC, Daniels D et al. A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. Annals of Oncology. 2017 Jan 1;28(1):121-127. https://doi.org/10.1093/annonc/mdw444
Agulnik, M. ; Costa, R. L B ; Milhem, M. ; Rademaker, A. W. ; Prunder, B. C. ; Daniels, D. ; Rhodes, B. T. ; Humphreys, C. ; Abbinanti, S. ; Nye, L. ; Cehic, R. ; Polish, A. ; Vintilescu, C. ; McFarland, T. ; Skubitz, K. ; Robinson, Steven ; Okuno, Scott Heitaka ; Van Tine, B. A. / A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. In: Annals of Oncology. 2017 ; Vol. 28, No. 1. pp. 121-127.
@article{a94de28599c8461895b245348eb7bf24,
title = "A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas",
abstract = "Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47{\%}) and 27 patients (46{\%}) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41{\%}) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6{\%}) and 30 (54.5{\%}) patients. The 16 week PFS rate was 36.4{\%} [95{\%} confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95{\%} CI 1.8-3). Median OS observed was 12.2 months (95{\%} CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3{\%}), hypertension (43.1{\%}), nausea (31{\%}) and diarrhea (27.6{\%}). The most common grade three toxicity was hypertension (22.4{\%}). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS.",
keywords = "Phase II, Sarcoma, Tivozanib, Tyrosine kinase inhibitor",
author = "M. Agulnik and Costa, {R. L B} and M. Milhem and Rademaker, {A. W.} and Prunder, {B. C.} and D. Daniels and Rhodes, {B. T.} and C. Humphreys and S. Abbinanti and L. Nye and R. Cehic and A. Polish and C. Vintilescu and T. McFarland and K. Skubitz and Steven Robinson and Okuno, {Scott Heitaka} and {Van Tine}, {B. A.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/annonc/mdw444",
language = "English (US)",
volume = "28",
pages = "121--127",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas

AU - Agulnik, M.

AU - Costa, R. L B

AU - Milhem, M.

AU - Rademaker, A. W.

AU - Prunder, B. C.

AU - Daniels, D.

AU - Rhodes, B. T.

AU - Humphreys, C.

AU - Abbinanti, S.

AU - Nye, L.

AU - Cehic, R.

AU - Polish, A.

AU - Vintilescu, C.

AU - McFarland, T.

AU - Skubitz, K.

AU - Robinson, Steven

AU - Okuno, Scott Heitaka

AU - Van Tine, B. A.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS.

AB - Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS.

KW - Phase II

KW - Sarcoma

KW - Tivozanib

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85015788678&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015788678&partnerID=8YFLogxK

U2 - 10.1093/annonc/mdw444

DO - 10.1093/annonc/mdw444

M3 - Article

C2 - 27771610

AN - SCOPUS:85015788678

VL - 28

SP - 121

EP - 127

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 1

ER -