Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase Itrial

Both replication-incompetent and replication-selective adenoviruses are bei ng developed for the treatment of cancer and other diseases. Concerns have been raised about the safety of intra-vascular adenovirus administration fo llowing a patient death on a clinical trial with a replication-defective ad enovirus. In addition, the feasibility of vascular delivery to distant tumo rs has been questioned. dl1520 (ONYX-015) is a replication-selective adenov irus that has previously shown safety and antitumoral activity following in tratumoral injection. This is the first report of intra-vascular administra tion with a genetically engineered, replication-selective virus. A phase I dose-escalation trial was performed in patients with liver-predominant gast rointestinal carcinoma (n = 11 total; primarily colorectal). dl1520 was inf used into the hepatic artery at doses of 2 x 10(8)-2 x 10(12) particles for two cycles (days 1 and 8). Subsequent cycles of dl1520 were administered i n combination with intravenous 5-fluorouracil (5-FU) and leucovorin. No dos e-limiting toxicity, maximally tolerated dose or treatment-emergent clinica l hepatotoxicity were identified following dl1520 infusion. Mild to moderat e fever, rigors and fatigue were the most common adverse events. Antibody t iters increased significantly in all patients. Viral replication was detect able in patients receiving the highest two doses. An objective response was demonstrated in combination with chemotherapy in a patient who was refract ory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery inf usion of the attenuated adenovirus dl1520 was well-tolerated at doses resul ting in infection, replication and chemotherapy-associated antitumoral acti vity.