First-in-human phase I clinical trial of QBI-139, a human ribonuclease variant, in solid tumors.
TPS3113 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. Variants of human ribonucleases (RNase) have been generated with diminished binding to their natural inhibitor inside cells, which allows the new proteins to kill cancer cells. QBI-139, a variant that retains 95% sequence identity to a naturally occurring RNase, has demonstrated efficacy as both a single agent and in combination against multiple tumor types in in vivo models of human cancer. A first in human phase I trial was designed and initiated for QBI-139. Methods: Since QBI-139 showed efficacy against multiple cancers in model systems, a first in human phase I trial was designed for patients with advanced solid tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion once weekly for a cycle of three weeks. In the absence of disease progression or unacceptable toxicity, treatment can continue on the twenty one day cycle. The trial is a standard 3+3 design with cohorts of three to six patients receiving escalating doses of QBI-139 until the maximum tolerated dose (MTD) and/or recommended phase II dose is determined. The inclusion/exclusion criteria are typical for the patient population. Forty three patients have been treated to date (January 2012) without identification of 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 50.4 mg/m2. Dose escalation is ongoing. The primary outcome is to evaluate the toxicity and tolerability of QBI-139 in patients with advanced refractory solid tumors. This information will allow for identification of the maximum tolerated dose. Clinical exposure levels are being monitored by measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139 will be measured using RECIST criteria. Since QBI-139 demonstrated broad efficacy in model systems, another outcome of the phase I trial may be identification of the indications for the next stage of clinical development.