Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma.

The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing's sarcoma. Clinical-grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85-92% was demonstrated in vitro in type 1 human Ewing's sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing's sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low- and high-dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing.

Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human tumor necrosis factor-α gene, with chemoradiotherapy in locally advanced esophageal cancer. OBJECTIVES: To assess pathologic complete response (pCR), time to disease progression, progression-free survival, survival, and safety and tolerance in patients treated with preoperative chemoradiation combined with endoscopy or EUS-guided intratumoral injection of TNFerade biologic. DESIGN/INTERVENTION: Five weekly injections of TNFerade biologic, dose-escalated logarithmically from 4 × 10(8) to 4 × 10(11) particle units (PU), were given in combination with cisplatin 75 mg/m(2) and intravenous 5-fluorouracil 1000 mg/m(2)/d for 96 hours on days 1 and 29, and concurrent radiation therapy to 45 Gy. Surgery was performed 9 to 15 weeks after treatment. SETTING: U.S. multicenter study. PATIENTS: Patients with stage II and III esophageal cancer were enrolled. MAIN OUTCOME MEASUREMENTS: Primary outcome measures were safety, feasibility, tolerability, and rate of pCR. Secondary outcome measures were overall survival (OS) and disease-free survival. RESULTS: Twenty-four patients with a median age of 61 years were enrolled; 88% of the patients were men, 21% were stage II, and 79% were stage III. Six (29%) had a pCR, observed among 21 patients (20 who underwent esophagectomy and 1 at autopsy). Dose-limiting toxicities were not observed. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). At the top dose of 4 × 10(11) PU, thromboembolic events developed in 5 of 8 patients. The median OS was 47.8 months. The 3- and 5-year OS rates and disease-free survival rates were 54% and 41% and 38% and 38%, respectively. LIMITATIONS: We included primarily adenocarcinoma. CONCLUSIONS: Preoperative TNFerade, in combination with chemoradiotherapy, is active and safe at doses up to 4 × 10(10) PU and is associated with long survival. This regimen warrants additional studies.

Irofulven demonstrates clinical activity against metastatic hormone-refractory prostate cancer in a phase 2 single-agent trial.

BACKGROUND: The primary objective of this study was to assess the antitumor activity of irofulven in patients with hormone-refractory prostate cancer by measuring a sustained decrease of 50% or greater in serum prostate-specific antigen (PSA) levels. PATIENTS AND METHODS: Forty-two patients (median age, 73 years) received at least 1 dose of 10.6 mg/m2 irofulven per day on days 1-5 of a 28-day course. Eligible patients had pathologically confirmed metastatic hormone-refractory adenocarcinoma of the prostate and had not received prior cytotoxic chemotherapy. RESULTS: Forty-two patients received a median of 3 courses of irofulven. Thirty-two patients received at least 2 courses of therapy and were evaluable for efficacy. Four patients (13%) achieved partial response, with a median duration of 2.9 months (range, 2.6-5.8 months). Twenty-seven patients (84%) had disease stabilization and 1 patient (3%) progressed on study. Median progression-free survival was 3.2 months (95% confidence interval, 2.3-4.2 months), with a median progression-free survival of 4.2 months (range, 3.5-6.9 months) for responders. Grade 4 toxicities consisted of thrombocytopenia, anemia, and neutropenia, occurring in 1 patient each. The most common treatment-related grade 3 nonhematologic toxicities included asthenia (19% of patients), vomiting (14%), nausea (12%), and infection without grade 3/4 neutropenia (10%). CONCLUSION: Irofulven shows activity in hormone-refractory prostate cancer and has an acceptable safety profile, warranting further investigation of this drug, particularly in combination therapies.

Rationale for a phase III study of erythropoietin as a neurocognitive protectant in patients with lung cancer receiving prophylactic cranial irradiation.

Recent meta-analysis of patients with small cell lung cancer has confirmed the effectiveness of prophylactic cranial irradiation in reducing the cumulative incidence of brain metastases and contributing to a significant increase in 3-year survival. Likewise, with increased median survivals being documented in patients with stage IIIA/B non-small cell lung cancer, there is evidence that the brain is emerging as a significant metastatic target site. Although prophylactic cranial irradiation is a reasonable option to explore, the potential for long-term neuropsychologic adverse effects is of concern in both diagnostic groups. Radiation-induced reactive oxygen intermediates and reactive nitrogen intermediates appear to play a major role in mediating this toxicity. Hypoxic stress results in a significant increase in erythropoietin (EPO) mRNA in mouse brain and, in two models, the administration of EPO improves performance function and prevents cognitive impairment. With the demonstration of EPO receptors in astrocytes, neurons, and brain capillary endothelial cells as well as the ability of EPO to cross the blood-brain barrier, a potential for EPO-mediated central nervous system radioprotection is postulated. The rationale and preliminary design for a phase III study of EPO as a neurocognitive protectant in patients with lung cancer receiving prophylactic cranial irradiation is presented.