Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.

BACKGROUND: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties. METHODS: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints. RESULTS: Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin. CONCLUSION: Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.

Phase I trial of PT-100 (PT-100), a cytokine-inducing small molecule, following chemotherapy for solid tumor malignancy.

PT-100 upregulates cytokine expression competitively inhibiting the dipeptidyl peptidase activity of fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV). This dose-escalation study was conducted to evaluate the safety of PT-100 in patients receiving myelosuppressive chemotherapy and to assess its effects on neutrophil recovery.PT-100 was administered orally for 7 days as a 200 microg, 400 microg, 800 microg, or 1,200 microg total daily dose (divided twice daily) to 6, 6, 17, and 5 patients, respectively. Patients received 2 cycles of chemotherapy: The first cycle served as each individual patient's control. Patients had to develop Grade 3+ neutropenia in Cycle 1 in order to receive PT-100 in Cycle 2. Most patients received PT-100 on Days 2-8 of chemotherapy in Cycle 2, except at 800 microg where an additional cohort (n = 8) was treated on a Days 5-11 schedule. Five of 7 patients receiving 800 microg on Days 2-8 experienced a >/=1-day improvement in Grade 3+ neutropenia in Cycle 2 versus Cycle 1. Overall, PT-100 was well tolerated. A reduction in chemotherapy-related nausea, vomiting, fatigue, alopecia, and diarrhea was noted in patients receiving PT-100. Edema/peripheral swelling, hypotension, hypovolemia, and dizziness were the most common nonhematologic adverse events considered related to PT-100. Two Grade 3 adverse events were considered related to PT-100: syncope (1,200 microg) and orthostatic hypotension (800 microg). A maximum tolerated dose was not reached. Given the accelerated neutrophil recovery, preclinical evidence of antitumor activity, and tolerable toxicities of PT-100, additional studies to optimize the PT-100 dosing schedule in patients receiving myelosuppressive chemotherapy are needed.

Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer.

PURPOSE: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer PATIENTS AND METHODS: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 x 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. RESULTS: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. CONCLUSION: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints.

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.