Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced K_trans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in K_trans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.

Jang BI, et al. Gut Liver. 2011 Dec;5(4):397-405. http://dx.doi.org/10.5009/gnl.2011.5.4.397

Population-based studies of adverse events are scarce. Our objective was to evaluate chemotherapy-associated adverse events among elderly colorectal cancer (CRC) patients treated in the community. Data on elderly patients aged ≥65 years diagnosed with CRC at any stage between 2003 and 2005 were obtained from the Surveillance, Epidemiology, and End Results (SEER)–Medicare Database. Of 46 692 patients assessed, 36 137 (77.4%) received no i.v. chemotherapy, 5472 (11.7%) received fluorouracil (5-FU) alone, 2284 (4.9%) received oxaliplatin-containing regimens, 1306 (2.8%) received bevacizumab-containing regimens but without oxaliplatin, and 1493 (3.2%) received other chemotherapy. Symptoms and laboratory test abnormalities were commonly found in elderly, even in those who had not received any i.v. chemotherapy. The addition of i.v. chemotherapy was associated with higher incidences of adverse events. Oxaliplatin-based regimens led to higher incidences in nausea, neutropenia, and neuropathy compared with 5-FU alone. Patients aged ≥70 years (n = 37 601, 80.5%) tended to experience higher rates of certain adverse events, including infection, anemia, delirium, and heart disease than patients aged 65–69 years (n = 9091, 19.5%). Among community-dwelling elderly with CRC, the addition of i.v. chemotherapy and advanced age were associated with increasing adverse events. Appropriate selection of patients and assessment of social support may be important.