CG7870 is a replication-selective oncolytic adenovirus genetically engineered to replicate preferentially in prostate tissue. In a previous phase I/II clinical trial of intraprostatic delivery of CG7870 for locally recurrent prostate cancer this virus was well tolerated. In this phase I study CG7870 was administered as a single intravenous infusion in a group-sequential dose escalation design (1 x 10(10) to 6 x 10(12) viral particles (vp)) to 23 patients with hormone-refractory metastatic prostate cancer. Flulike symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common adverse events. Three therapy-related grade 3 adverse events were reported, one of which (fatigue) was serious. At doses greater than 10(12) vp all five patients experienced asymptomatic grade 1 to 2 transaminitis and/or isolated d-dimer elevations starting on day 2 through 8; dose escalation was therefore halted at 6 x 10(12) vp. All tested patients had CG7870 genomes present in the peripheral blood for at least 90 minutes after infusion; patients in the highest dose group had persistence of genomes through 29 days. A "secondary" or "delayed" peak in plasma CG7870 genome copies (defined as a >10-fold increase in CG7870 genomes from nadir concentration) suggestive of active viral replication and shedding into the bloodstream was detected in 16/23 (70%) patients. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in interleukins 6 and 10 (IL-6, IL-10) blood levels were detected. The peak IL-6 concentration after CG7870 treatment was associated with a transient, asymptomatic decrease in blood pressure. No partial or complete prostate-specific antigen (PSA) responses were observed; however, 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment, including 3 of 8 patients at the highest dose levels.

Perifosine (NSC 639966) is a synthetic, substituted heterocyclic alkylphosphocholine that acts primarily at the cell membrane targeting signal transduction pathways. Early clinical trials were limited because of dose-limiting gastrointestinal toxicity, and parenteral dosing of this class of agents is not possible because of their hemolytic properties; therefore, related compounds with an improved therapeutic index were developed. Toxicity was minimized and efficacy improved by using a loading dose/maintenance dose schedule, and therefore, this schedule was carried into clinical trials. This phase I trial enrolled 42 patients with incurable solid malignancies. The starting doses were 100 mg p.o. ؋ four doses (every 6 hours) load followed by a 50 mg p.o. once daily maintenance dose with escalation of either component in successive dose levels. No treatment related deaths occurred. The maximum-tolerated dose was determined to be 150 mg p.o. ؋ four doses load and 100 mg p.o. once daily maintenance. Dose-limiting toxicities such as nausea, diarrhea, dehydration, and fatigue were seen early during the loading phase and were surmountable with the use of prophylactic 5-HT 3 receptor antagonists, dexamethasone, and loperamide. Toxicities during the chronic phase were difficult to manage and, given that pharmacokinetic data showed biologically active serum concentrations (based on preclinical data), raised the question of less frequent maintenance dosing. Pharmacokinetic data confirmed the maintenance of stable drug levels with chronic dosing and the long half-life. One partial response was seen, as were multiple patients with stable disease beyond course 2. These results suggest perifosine activity in sarcoma and perhaps renal cell carcinoma (stable disease in two patients who continued for 6 and 14 courses), thus justifying additional investigation of this agent in a phase II sarcoma trial.

Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.

Purpose Several cytotoxic chemotherapy regimens are active against metastatic breast cancer; however, benefits are modest and overall prognosis remains limited. For anthracycline and taxane-pretreated metastatic breast cancer, there remains a relative paucity of therapies with significant activity. This Phase II study evaluated the combination of capecitabine and oxaliplatin (XELOX) among patients with metastatic breast cancer being treated in the first or second-line setting. Methods Patients received oxaliplatin 85 mg/m2 on days 1 and 15, and capecitabine 1500 mg/m2 twice daily on days 1-7 and 15-21 of a 28 day cycle. Patients were treated until progression or intolerable toxicity. The primary objective was to estimate the objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria with tumor assessments every 8 weeks. Results 10 patients were treated of which 3 had received prior neurotoxic therapy in the metastatic setting. There were no confirmed complete responses, 5 patients had partial response, 4 patients had stable disease for at least 24 weeks, and one patient was unevaluable. Median time to progression (TTP) was 10.4 months (95% lower confidence bound [LCB]: 5.75 months), median progression free survival (PFS) was 14.2 months (95% LCB: 6.14 months), and median overall survival (OS) was 19 months (95% LCB: 12.8 months). Multiple patients experienced pain syndromes and unusual neuropathies. Other common toxicities included fatigue, diarrhea, and nausea. Conclusions XELOX is a promising regimen for anthracycline-pretreated metastatic breast cancer although careful patient selection is indicated and alternate dosing schedules should be explored to minimize neurologic morbidity.