Purpose Angiogenesis inhibition has emerged as a potentially promising treatment strategy for neuroendocrine tumors. 2-Methoxyestradiol (2ME2; Panzem®) is a natural derivative of estradiol with demonstrated anti-angiogenic activity in animal models. We performed a prospective, phase II study of 2ME2, administered in combination with bevacizumab, in patients with advanced carcinoid tumors. Methods Thirty-one patients with advanced carcinoid tumors were treated with 2ME2, administered orally at a dose of 1,000 mg four times daily. Patients also received bevacizumab 5 mg/kg intravenously every 2 weeks. Patients were observed for evidence of toxicity, tumor response, and survival. Results The combination of 2ME2 and bevacizumab was relatively easily tolerated and was associated with anticipated toxicities for these two agents. No confirmed radiologic responses (by RECIST) were observed. However, 68% of the radiologically evaluable patients experienced at least some degree of tumor reduction, and the median progression-free survival (PFS) time was 11.3 months. Conclusion 2ME2 and bevacizumab can be safely administered to patients with advanced carcinoid tumors. While major tumor regression was not observed with this regimen, the encouraging median progression-free survival time suggests that this regimen has some degree of anti-tumor activity and supports the further investigation of angiogenesis inhibitors in this disease.

Background Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond the first-line gemcitabine/platinum-based chemotherapy. We performed a single arm phase II and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against VEGFR2 and MET, in patients with advanced refractory cholangiocarcinoma. Methods Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib 60 mg orally daily continuously. The primary endpoint was progression free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated. Results The study enrolled 19 patients with cholangiocarcinoma (female 68%; median age 67yo; intra- vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95%CI; 1.6, 5.4), and the median overall survival was 5.2 months (95%CI; 2.7, 10.5). Grade 3/4 adverse events occurred in 89% of patients, and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistula (5%), and hypertension (11%). One patient with 3+ MET expression in the tumor stayed on treatment for 278 days, but MET expression did not correlate with outcomes in the overall study population. Plasma VEGF, PlGF and SDF1α increased and soluble VEGFR2 and Ang2 decreased after treatment (all p<0.01). Plasma TIMP-1 inversely correlated with PFS, and soluble MET (sMET) and IL-6 inversely correlated with OS. Conclusions In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, one patient with a MET-high tumor had prolonged benefit from treatment. Baseline plasma sMET was associated with OS. Any further development of this drug in cholangiocarcinoma should include dose reduction and a biomarker-driven approach.

Summary Background Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. Methods We did a parallel cohort study of patients with metastatic or locally advanced grade 1–2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. Findings Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21.9%, 95% CI 11.0–38.8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). Interpretation Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. Funding US National Cancer Institute of the National Institutes of Health.

Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.