A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors.

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study.

PURPOSE: This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to alpha(5)beta(1) integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of alpha5beta1 sites on peripheral blood monocytes. RESULTS: Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte alpha5beta1 integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months). CONCLUSIONS: Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.

Iseganan HCl: a novel antimicrobial agent.

Iseganan HCl is an antimicrobial peptide under development for the prevention of oral mucositis, a severe consequence of some chemotherapy and radiation therapy regimens. Several attributes of iseganan make it an optimal candidate for study in this clinical situation where both local and systemic host defenses may be impaired. These include broad spectrum and rapid bactericidal activity, a lack of observed resistance and cross-resistance and stability in biological fluids. Clinical trials of patients receiving stomatotoxic chemotherapy followed by a haematopoietic stem cell transplant show iseganan reduces the occurrence of oral mucositis and ameliorates sequelae such as mouth pain, throat pain and difficulty swallowing. Iseganan is well-tolerated, which is partly attributable to a lack of systemic absorption following topical oral administration. Other promising areas of investigation include topical oral application for the prevention of ventilator-associated pneumonia and nebulisation for treatment of chronic lung infection in patients with cystic fibrosis. Future studies will expand on the role of iseganan as a novel antimicrobial.