Randomised phase II study of docetaxel plus vandetanib versus docetaxel followed by vandetanib in patients with persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: SWOG S0904.
BACKGROUND
Vandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).


METHODS
Women with refractory or progressive OC were randomised 1:1 to docetaxel (75 mg/m(2), IV)+vandetanib (100mg daily, PO, D+V) or docetaxel (75 mg/m(2), D). Up to three additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary end-point was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D → V).


RESULTS
131 Patients were enrolled; two were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D+V) versus 3.5 (D); HR: 0.99 (80% CI: 0.79-1.26). 61 Patients on D+V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily haematologic. Similarly, 17 (27%) of 64 patients receiving D had G4 events, primarily haematologic. 27 Evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhoea was observed in 4% D → V patients. Median OS was 14 mos (D+V) versus 18 mos (D → V); HR(OS): 1.25 (80% CI: 0.93-1.68). Crossover vandetanib response was 4% (1/27 evaluable patients). High plasma IL-8 levels were associated with response to D+V.


CONCLUSIONS
Combination docetaxel+vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.
University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address: rcoleman@mdanderson.org.
Robert L
RL
Coleman
SWOG Statistical Center, Seattle, WA, USA.
James
J
Moon
University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Anil K
AK
Sood
University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Wei
W
Hu
Wichita CCOP/Associates in Women's Health, Wichita, KS, USA.
James E
JE
Delmore
Cancer Research for the Ozarks-Cox Health, Springfield, MO, USA.
Albert J
AJ
Bonebrake
SWOG Statistical Center, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Garnet L
GL
Anderson
Arizona Cancer Center, Tucson, AZ, USA.
Setsuko K
SK
Chambers
Cancer Treatment Centers of America, Zion, IL, USA.
Maurie
M
Markman
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D000077143:Docetaxel; D005185:Fallopian Tube Neoplasms / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000097:blood / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D010880:Piperidines; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; C452423:vandetanib
Chemotherapy; Clinical trial; Epithelial cancer; Fallopian tube cancer; Ovarian cancer; Primary peritoneal cancer; Randomised phase II; Taxanes; Vandetanib