Background: Prognosis for patients with recurrent and/or metastatic squamous cell cancer of the head and neck (R/M-SCCHN) is very poor. αvβ5 integrin is overexpressed in SCCHN and selective integrin blockade is being investigated as a treatment strategy. Methods: ADVANTAGE was a phase I/II study evaluating cilengitide with cetuximab and platinum-based chemotherapy. Eligible patients were ≥18 years with ≥1 measurable lesion, Karnofski performance status ≥70%, and confirmed R/M-SCCHN. The phase II part reported herein was an open-label, randomized, controlled trial investigating progression-free survival (PFS) in patients treated with 2 cilengitide 2000 mg regimens: once weekly (CIL1W) and twice weekly (CIL2W) administration combined with cisplatin, 5-FU, and cetuximab (PFE) as compared with PFE alone (control). Secondary objectives included overall survival (OS) and objective response (OR). Treatment-emergent adverse events (TEAEs) were monitored. Results: 184 eligible patients were enrolled. Overall, patient characteristics were similar across arms. Median duration of treatments was shorter in the CIL2W arm compared with the CIL1W arm (cilengitide: 16.1 vs 23.4 wk, cetuximab: 16.0 vs 22.6 wk, platinum: 16.0 vs 18.0 wk, and 5-FU: 14.6 vs 18.0 wk). Median PFS was 6.4 months in the CIL1W group, 5.6 months in the CIL2W group and 5.7 months in the control group, with CIL1W and CIL2W having HRs of 1.03 (95% CI: 0.67–1.59) and 1.55 (95% CI: 0.99–2.43) vs control. The latter HR was possibly due to less compliance in the CIL2W arm. Median OS was 12.4, 10.6, and 11.6 months in the CIL1W, CIL2W, and control groups, respectively. ORs were observed in 46.8%, 26.7%, and 35.5% of patients in the CIL1W, CIL2W, and control arms, respectively. Most common (≥15%) grade 3/4 TEAEs were neutropenia, hypokalemia, leukopenia, stomatitis, and fatigue. No safety differences were noted between treatment arms. Overall, there were 7 drug-related TEAEs (2 in CIL1W, 2 in CIL2W, and 3 in control) leading to death. Conclusions: In this population, neither of the cilengitide-containing regimens was able to demonstrate a PFS benefit over PFE alone.