Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer: A randomized clinical trial

Debra L. Richardson, Michael W. Sill, Robert L. Coleman, Anil K. Sood, Michael L. Pearl, Siobhan M. Kehoe, Michael E. Carney, Parviz Hanjani, Linda Van Le, Xun C. Zhou, Angeles Alvarez Secord, Heidi J. Gray, Lisa M. Landrum, Heather A. Lankes, Wei Hu, Carol Aghajanian

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

IMPORTANCE: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). OBJECTIVE: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects. INTERVENTIONS: All patients received paclitaxel 80mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800mg orally daily or placebo. MAIN OUTCOMES AND MEASURES: The primary end pointwas PFS. The studywas designed to detect a 37.5%reduction in the hazard with 80% power (α = 10%). RESULTS: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95%CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively. CONCLUSIONS AND RELEVANCE: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer.

Original languageEnglish (US)
Pages (from-to)196-202
Number of pages7
JournalJAMA oncology
Volume4
Issue number2
DOIs
StatePublished - Feb 1 2018

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Paclitaxel
Ovarian Neoplasms
Randomized Controlled Trials
Disease-Free Survival
Hypoxia-Inducible Factor 1
Survival
Placebos
pazopanib
Interleukin-8
Single Nucleotide Polymorphism
Genotype
Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor-1
Platelet-Derived Growth Factor Receptors
Vascular Endothelial Growth Factor Receptor-2
Translational Medical Research
Proto-Oncogenes
Fallopian Tubes
Poisons
Receptor Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer : A randomized clinical trial. / Richardson, Debra L.; Sill, Michael W.; Coleman, Robert L.; Sood, Anil K.; Pearl, Michael L.; Kehoe, Siobhan M.; Carney, Michael E.; Hanjani, Parviz; Van Le, Linda; Zhou, Xun C.; Secord, Angeles Alvarez; Gray, Heidi J.; Landrum, Lisa M.; Lankes, Heather A.; Hu, Wei; Aghajanian, Carol.

In: JAMA oncology, Vol. 4, No. 2, 01.02.2018, p. 196-202.

Research output: Contribution to journalArticle

Richardson, DL, Sill, MW, Coleman, RL, Sood, AK, Pearl, ML, Kehoe, SM, Carney, ME, Hanjani, P, Van Le, L, Zhou, XC, Secord, AA, Gray, HJ, Landrum, LM, Lankes, HA, Hu, W & Aghajanian, C 2018, 'Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer: A randomized clinical trial', JAMA oncology, vol. 4, no. 2, pp. 196-202. https://doi.org/10.1001/jamaoncol.2017.4218
Richardson, Debra L. ; Sill, Michael W. ; Coleman, Robert L. ; Sood, Anil K. ; Pearl, Michael L. ; Kehoe, Siobhan M. ; Carney, Michael E. ; Hanjani, Parviz ; Van Le, Linda ; Zhou, Xun C. ; Secord, Angeles Alvarez ; Gray, Heidi J. ; Landrum, Lisa M. ; Lankes, Heather A. ; Hu, Wei ; Aghajanian, Carol. / Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer : A randomized clinical trial. In: JAMA oncology. 2018 ; Vol. 4, No. 2. pp. 196-202.
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abstract = "IMPORTANCE: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). OBJECTIVE: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects. INTERVENTIONS: All patients received paclitaxel 80mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800mg orally daily or placebo. MAIN OUTCOMES AND MEASURES: The primary end pointwas PFS. The studywas designed to detect a 37.5{\%}reduction in the hazard with 80{\%} power (α = 10{\%}). RESULTS: A total of 106 women (median age [range], 61 [35-87] years; 88 [83{\%}] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8{\%}) vs 10 of 44 (22.7{\%}) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90{\%} CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90{\%} CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95{\%}CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4{\%}] vs 17 of 54 [31.5{\%}]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37{\%}] vs 5 of 52 [9.6{\%}]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7{\%}), 3 of 15 (20{\%}), and 4 of 8 (50{\%}) responding, respectively. CONCLUSIONS AND RELEVANCE: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer.",
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TY - JOUR

T1 - Paclitaxel with and without pazopanib for persistent or recurrent ovarian cancer

T2 - A randomized clinical trial

AU - Richardson, Debra L.

AU - Sill, Michael W.

AU - Coleman, Robert L.

AU - Sood, Anil K.

AU - Pearl, Michael L.

AU - Kehoe, Siobhan M.

AU - Carney, Michael E.

AU - Hanjani, Parviz

AU - Van Le, Linda

AU - Zhou, Xun C.

AU - Secord, Angeles Alvarez

AU - Gray, Heidi J.

AU - Landrum, Lisa M.

AU - Lankes, Heather A.

AU - Hu, Wei

AU - Aghajanian, Carol

PY - 2018/2/1

Y1 - 2018/2/1

N2 - IMPORTANCE: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). OBJECTIVE: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects. INTERVENTIONS: All patients received paclitaxel 80mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800mg orally daily or placebo. MAIN OUTCOMES AND MEASURES: The primary end pointwas PFS. The studywas designed to detect a 37.5%reduction in the hazard with 80% power (α = 10%). RESULTS: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95%CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively. CONCLUSIONS AND RELEVANCE: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer.

AB - IMPORTANCE: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). OBJECTIVE: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects. INTERVENTIONS: All patients received paclitaxel 80mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800mg orally daily or placebo. MAIN OUTCOMES AND MEASURES: The primary end pointwas PFS. The studywas designed to detect a 37.5%reduction in the hazard with 80% power (α = 10%). RESULTS: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95%CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively. CONCLUSIONS AND RELEVANCE: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer.

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