A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma.

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 Ktrans (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 Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

Molecular mechanisms in cancer: what should clinicians know?

Normal cells are influenced by a variety of environmental and host influences that can produce pro-carcinogenic mutations. Either a single or a series of mutations might result in cellular transformation. Like normal cells, most cancer cells use multiple redundant intracellular signaling pathways to ensure the maintenance and viability of functions critical to their survival. Thus, cellular pathways that are integral to cell function, survival, proliferation, and receptor expression are potential targets for therapeutic intervention. One example of this is the epidermal growth factor receptor signaling pathway. Other potential targets are molecules that mediate processes through which tumors produce angiogenic and invasion factors that stimulate host blood vessel growth into tumors and allow tumor growth and metastasis, such as the vascular endothelial growth factor. Targeting of downstream events that result in cellular apoptosis is another potential strategy. Continued investigations may result in the development of proteomic profiling databases through which a patient might be matched with molecular signatures in a library and upon which individualized cancer therapies might be selected. In this way, clinicians might recommend combinations of molecularly targeted agents and other therapies on the basis of an individual patient's proteomic profile.

A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer. EXPERIMENTAL DESIGN: Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by squalamine as a continuous infusion on days 1-5, every 21 days. RESULTS: A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of squalamine was 100 mg/m(2)/day and escalated to 400 mg/m(2)/day; two of three patients at 400 mg/m(2)/day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m(2)/day was selected as the Phase II dose of squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m(2)/day. There was no pharmacokinetic evidence of drug interactions for the combination of squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%. CONCLUSIONS: The combination of squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.

Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer.

PURPOSE: Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions. PATIENTS AND METHODS: Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity. RESULTS: The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy. CONCLUSION: The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.