Profile of pazopanib and its potential in the treatment of epithelial ovarian cancer

Figures & data

Figure 1 Inhibition of angiogenic pathways: targeting multiple angiogenic ligands and cell membrane receptors.

Notes: Tumor and host endothelial cells release angiogenic ligands that interact in an autocrine and paracrine fashion. Bevacizumab targets the VEGF ligand and inhibits VEGF-induction of VEGF receptors. Trebananib binds Ang1 and Ang2 ligands, inhibiting binding to the TIE receptor thus preventing activation of the angiopoietin pathway. TKI target and inhibit the intracellular component of multiple cell membrane tyrosine kinase receptors (PDGF, VEGF, and FGF receptors).
Abbreviations: PDGF, platelet derived growth factor; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; Ang1, angiopoietin-1; Ang2, angiopoietin-2; TIE, tyrosine kinase with immunoglobulin-like and EGF-like domains 1; TKI, tyrosine kinase inhibitors.

Table 1 Completed Phase I trials of pazopanib in solid tumors, including epithelial ovarian cancer

Trial	Setting	Treatment	RR, %	SD, %	Grade 3 or 4 adverse events
Hurwitz et al^Citation50 (n=63, ovarian =1)	Advanced relapsed or refractory solid tumors	Pazopanib monotherapy; no MTD	5	22	Hypertension (G3, n=16), diarrhea (G3, n=3), proteinuria (G3, n=2), nausea (G3, n=1), fatigue (G3, n=1), neutropenia (G3, n=2)
de Jonge et al^Citation53 (n=75, ovarian =3)	Advanced solid tumors	MTD: pazopanib 800 mg/day + lapatinib 1,500 mg/day	5	16	ALT increase (G3, n=1), neutropenia (G3, n=1), fatigue (G3, n=1), GIB (G5, n=1), decreased LVEF (G3, n=2), confusion (G3, n=1)
Kerklaan et al^Citation54 (n=28, ovarian =5)	Advanced solid tumors	Pazopanib 800 mg/day + oral topotecan 10 mg (days 1, 8, 15)	9	57	Anemia (G3, n=3), leukocytopenia (G3, n=2), neutropenia (G3, n=2), fatigue (G3, n=2), hand foot syndrome (G3, n=1)
Dy et al^Citation90 (n=33, ovarian =2)	Advanced solid tumor after failing standard therapy	MTD: pazopanib 600 mg/day + erlotinib 150 mg/day	12	38	Diarrhea (G3, n=2), hypertension (G3, n=1), liver-enzyme elevation (G3, n=5), nausea (G3, n=2), lymphopenia (G3, n=4), rash (G3, n=1)
Fasolo et al^Citation91 (n=53, ovarian =10)	Advanced solid tumors with indication for anthracycline treatment	Pazopanib 200–800 mg days 1–8 + epirubicin 75–90 mg/m^2 every 3 weeks	12	31	Neutropenia (G3/4, n=35), nausea/vomiting (G3/4, n=4), fatigue (G3/4, n=3), anemia (G3/4, n=2)
Plummer et al^Citation55 (n=22, ovarian =1)	Advanced solid tumor, progressed on standard therapy	MTD not determined; max dose pazopanib 800 mg/day + gemcitabine 1,250 mg/m^2 days 1 and 8 every 3 weeks	5	67	Neutropenia/thrombocytopenia (G4, n=7), fatigue (G3, n=1), increased ALT (G3, n=1), pneumonia (G5, n=1)
Tan et al^Citation52 (n=26, ovarian =1)	Metastatic solid tumor, ≤3 prior regimens	MTD: pazopanib 800 mg/day + paclitaxel 80 mg/m^2 days 1, 8, 15 every 28 days	19	58	Diarrhea (G3/4, n=2), elevated liver enzymes (G3/4, n=4), hypertension (G3/4, n=1), neutropenia (G3/4, n=3), peripheral neuropathy (G3/4, n=1)

Abbreviations: RR, response rate; SD, stable disease; MTD, maximum tolerated dose; ALT, alanine transaminase; LVEF, left ventricular ejection fraction.

Table 2 Completed Phase II/III trials of pazopanib in epithelial ovarian carcinoma

Trial	Setting	Treatment	RR, %	SD, %	PFS, months	OS, months	Grade 3/4 adverse events
Friedlander et al,^Citation55 Phase II (n=36)	Recurrent EOC, PPC, or FTC; ≤2 prior regimens	Pazopanib 800 mg/day	31	56	NR	NR	Hypertension (G3, n=1), diarrhea (G3, n=3), fatigue (G3, n=4), elevated liver enzymes (G3, n=8), peripheral edema (G4, n=1)
duBois et al,^Citation19 Phase I/II (n=12)*	New diagnosis, advanced gynecologic tumors	Pazopanib 800 mg/day + carboplatin (AUC 5) + paclitaxel (175 mg/m^2) every 3 weeks	NR	NR	NR	NR	GIP (G4/5, n=2), abdominal cramps (G3, n=1)
Oaknin et al,^Citation60 Phase II (n=25)	Recurrent, platinum resistant EOC, FTC, or PPC; ≤2 prior regimens	Pazopanib 800 mg/day	4	36	1.83	NR	Hypertension (G3, n=6), elevated liver enzymes (G3, n=3), asthenia (G3, n=2), DVT (G3, n=1), fistula (G3, n=1), anemia (G3, n=1)
duBois et al,^Citation17 Phase III (n=940)	Advanced stage EOC, PPC, or FTC	Pazopanib 800 mg/day versus placebo as maintenance after first-line chemotherapy	NR	NR	17.9 versus 12.3	NR	Hypertension (G3/4, n=147), liver toxicity (G3/4, n=45), neutropenia (G3/4, n=47), diarrhea (G3/4, n=39), fatigue (G3/4, n=13), thrombocytopenia (G3/4, n=12), hand–foot syndrome (G3/4, n=9)
Zang et al,^Citation66 Phase III (n=145)	Asian women; advanced stage EOC, PPC, or FTC	Pazopanib 800 mg/day versus placebo as maintenance after first-line chemotherapy	NR	NR	18.1 versus 18.1	NR	Hypertension (G3, n=13), neutropenia (G3, n=9), diarrhea (G3, n=5), thrombocytopenia (G3, n=3), elevated liver enzymes (G3, n=2), leukopenia (G3, n=1)

Note:

* Study discontinued given significant dose-limiting toxicities.

Abbreviations: RR, response rate; SD, stable disease; PFS, progression-free survival; OS, overall survival; EOC, epithelial ovarian cancer; AUC, area under the curve; PPC, primary peritoneal carcinoma; FTC, fallopian tube cancer; DVT, deep vein thrombosis; GIP, gastrointestinal perforation; NR, not reported.

Table 3 Pazopanib and epithelial ovarian carcinoma: clinical trials actively recruiting patients

Trial	Phase	Estimated enrollment	Regimen	Setting	Primary objective
NCT01608009^Citation85	Phase I	17	Pazopanib → pazopanib + IV paclitaxel → pazopanib maintenance	Recurrent, platinum-resistant EOC	Change in ^18F-fluciclatide-retention parameters
NCT01600573^Citation61	Phase I/II	68	Pazopanib + topotecan	Recurrent, platinum-resistant EOC	I: MTD II: PFS
NCT01238770^Citation60	Phase I/II	57	Pazopanib + cyclophosphamide	Recurrent, platinum-resistant EOC, PPC, or FTC	I: MTD II: RR
NCT01402271^Citation86	Phase I/II	96	Pazopanib + carboplatin + paclitaxel	Recurrent, platinum-resistant EOC, PPC, or FTC	I: MTD II: PFS
NCT01644825^Citation62	Phase II	72	IV paclitaxel ± pazopanib	Recurrent, platinum-resistant EOC	PFS
NCT01392352^Citation64	Phase II	52	Pazopanib	Solid tumors, including ovarian cancer	Change in endothelial dependent function
NCT01610206^Citation56	Phase II	142	Gemcitabine ± pazopanib	Recurrent EOC, FTC, or PPC	PFS

Abbreviations: MTD, maximum tolerated dose; PFS, progression free survival; RR, response rate; EOC, epithelial ovarian cancer; PPC, primary peritoneal carcinoma; FTC, fallopian tube carcinoma; IV, intravenous.

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