Importance Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade with ipilimumab prolongs survival in metastatic melanoma patients. CTLA-4 blockade and granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor vaccine combinations demonstrate therapeutic synergy in pre-clinical models. A key issue is whether systemic GM-CSF synergizes with CTLA-4 blockade. Objective To compare the effect of sargramostim plus ipilimumab vs ipilimumab alone on overall survival in patients with metastatic melanoma. Design, Setting, and Participants A phase II randomized clinical trial was conducted in the United States by Eastern Cooperative Oncology Group between December 28, 2010 and July 28, 2011. Patients with unresectable stage III or IV melanoma, ≥one prior therapy, no CNS metastases, and ECOG performance status 0/1 were eligible. Interventions Patients were randomized to ipilimumab 10 mg/kilogram intravenously day 1 plus sargramostim 250 μg subcutaneously days 1-14 of 21 day cycles versus ipilimumab alone. Ipilimumab treatment included induction for four cycles followed by maintenance every fourth cycle. Main Outcomes and Measures Primary was comparison of the length of overall survival. Secondary was progression-free survival, response rate, safety, and tolerability. Results A total of 245 patients were treated. Median follow-up was 13.3 months (range; .03-19.9). Median overall survival for sargramostim plus ipilimumab was 17.5 months (95% CI; 14.9, not reached) compared to 12.7 months (95% CI; 10.0, not reached) for ipilimumab. One-year survival rate for sargramostim was 68.9% (95% CI; 60.6%, 85.5%) compared to 52.9% (95% CI; 43.6%, 62.2%) with ipilimumab (stratified logrank one-sided P=.01; mortality hazard ratio .64, one-sided 90% repeated CI (not applicable, .90)). A planned interim analysis was conducted at 69.8% (104 observed/ 149 planned deaths) information time. O'Brien-Fleming boundary was crossed for improvement in overall survival. There was no difference in progression-free survival. Median progression free survival for ipilimumab+sargramostim was 3.1 months (95% CI; 2.9, 4.6) and for ipilimumab was 3.1 months (95% CI; 2.9, 4.0). Grade 3-5 adverse events occurred in 44.9% (95% CI; 35.8%, 54.4%) of sargramostim plus ipilimumab and 58.3% (95% CI; 49.0%, 67.2%) of ipilimumab alone (two-sided P=.04). Conclusion and Relevance Among patients with unresectable stage III or IV melanoma, treatment with sargramostim plus ipilimumab, compared to ipilimumab alone, resulted in longer overall survival and lower toxicity, but no difference in progression free survival. These findings require confirmation in larger sample sizes and longer follow up.

TPF induction chemotherapy can be delivered safely with a cisplatin dose of 100 mg/m(2) in previously untreated patients with SCCHN. The regimen is associated with a high rate of primary site clinical and pathologic CRs. Phase III comparison with cisplatinum and fluorouracil chemotherapy is warranted.

We demonstrate that noncovalent ion-pair interactions in solution can be employed to control the molecular spacing of thiols in a self-assembled monolayer (SAM) on gold. Ion-pairs formed between the carboxylate tail-group of 16-mercaptohexadecanoic acid (MHA) and tetraalkylammonium (TAA+) hydroxide salts of various alkyl side-chain lengths remain intact during chemisorption of the thiol on gold. The resulting ion-pair SAMs exhibit a 1:1 molar ratio of MHA:TAA+ on the surface and are covalently bound to the gold surface through the thiol headgroup of MHA. We hypothesize that the incorporation of the bulky TAA+ group competes with the strong tendency of the thiols to organize into an ordered monolayer, which highlights the strength of the ion-pair complexes. The ion-pair films can be converted into a loosely packed MHA monolayer by rinsing the SAM with a solution of potassium perchlorate, which releases the TAA+ from the surface. Contact angle measurements and X-ray spectroscopy (XPS) confirm the stoichiometry and covalent attachment of the monolayers. XPS analysis and contact angle measurements indicate that the surface density of bound MHA decreases with increasing size of the TAA+ cation. These results suggest that steric hindrance created by the bulky side-chains of the TAA+ cation dictates the lateral spacing of MHA chains on the surface.