The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.
Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.
Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.
Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.
Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.
Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.
The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.
The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.
Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.