A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer.

PURPOSE: We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A total of 35 patients received single or multiple (every 28 days × 3 or weekly × 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 × 10(12), 3 × 10(12), 1 × 10(13) or 3 × 10(13) viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status. RESULTS: Grade 1-2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly × 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11). CONCLUSIONS: Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested.

A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia.

To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit, investigators involved in this multicenter, phase II, placebo-controlled study randomized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0, 2, and 4 and then every 4 weeks to week 24; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0-6 and then for 3 of every 4 weeks until their disease progressed. The primary endpoint was change in lean body mass (LBM) at 8 weeks from baseline; major secondary endpoints included overall survival, progression-free survival, Karnofsky performance status, and 6-minute walk test distance. In addition, quality of life was measured. The mean change in LBM at 8 weeks was +0.4 kg for patients receiving placebo, +0.3 kg for those receiving 3 mg/kg of infliximab, and +1.7 kg for those receiving 5 mg/kg of infliximab. No statistically significant differences in LBM or secondary endpoints were observed among the groups. Safety findings were similar in all groups. Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo.

Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology.

PURPOSE: Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non-small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. PATIENTS AND METHODS: Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second >or= 1 L, and less than 5% weight loss. Patients received P 50 mg/m(2) intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m(2) IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m(2) IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). RESULTS: On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). CONCLUSION: Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

Phase 1 study of escalating-dose OncoGel (ReGel/paclitaxel) depot injection, a controlled-release formulation of paclitaxel, for local management of superficial solid tumor lesions.

OncoGel is a novel depot formulation of paclitaxel designed for intralesional injection with a sustained paclitaxel delivery over approximately 6 weeks from a single administration. This phase 1 study was designed to characterize the toxicity, pharmacokinetics and preliminary antitumor activity associated with OncoGel administered directly into solid tumors. OncoGel was injected into 18 superficially accessible advanced solid cancerous lesions among 16 adult patients for whom no curative therapy was available. Four dose cohorts were evaluated, ranging from 0.06 to 2.0 mg paclitaxel/cm3 tumor volume. OncoGel injections were generally well tolerated. There was one report of grade 3 injection site pain for a patient in the 0.25 mg paclitaxel/cm3 tumor volume dose cohort. Other adverse events considered related to the study drug included mild to moderate local responses to the injection itself. Systemic levels of paclitaxel were detectable only in 3.3% of the samples analyzed (range: 0.53-0.71 ng/ml). For the 14 patients evaluable for disease progression, stable disease was noted among six patients and progressive disease among eight patients. Although the maximum tolerated dose was not identified, the planned maximum dose was administered in the study. OncoGel delivered intralesionally at doses up to 2.0 mg paclitaxel/cm3 tumor volume was well tolerated and paclitaxel remained localized at the injection site, confirming design principles to minimize systemic exposure. Therefore, localized paclitaxel administration using OncoGel merits continued clinical development.