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A phase I clinical trial of QBI-139, a human ribonuclease variant, in solid tumors.

TPS146 Background: RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. A series of human ribonuclease (RNase) variants have been generated with diminished binding to their natural inhibitor inside cells, which allows the new proteins to kill cancer cells. One of these RNases, called QBI-139, has shown efficacy against multiple tumor types in in vivo models of human cancer and was selected for a first in human clinical trial.


METHODS
Since QBI-139 showed efficacy against multiple cancers in model systems, a Phase I trial was designed for patients with advanced solid tumors ( NCT00818831 ). Patients receive QBI-139 by intravenous infusion once weekly for three weeks with treatment repeating every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of three to six patients receive escalating doses of QBI-139 until the maximum tolerated dose (MTD) is determined. The inclusion/exclusion criteria are typical for the patient population. Twenty-nine patients have been treated to date (January 2011) without reaching dose limiting toxicity. The starting dose in the clinical trial was 3 mg/m2 while the most recently completed cohort was treated with a dose of 18.6 mg/m2. Dose escalation is ongoing. The primary outcomes of the trial are to evaluate the toxicity and tolerability of and the maximum tolerated dose for QBI-139 in patients with advanced refractory solid tumors. In addition, patient response to QBI-139 will be measured using the RECIST criteria and the pharmacokinetics of QBI-139 will be evaluated. Given the agent's broad efficacy in model systems, one of the goals of the Phase I trial is to identify indications for the next clinical trial of QBI-139.