Abstract B158: Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study

Introduction: Crotoxin is a neurotoxic phospholipase isolated from the venom of a rattlesnake. It has proven to have significant and broad acting anti‐tumor activity: in previous phase 1 clinical studies, comprising 60 enrolled patients, clinical benefit was observed in 26 patients (43%). Traditional designs were used, the dose‐limiting toxicity (DLT) being neuromuscular toxicity. Preclinical animal data suggests that, by using a dose escalation protocol, the administration of very high doses can be achieved without adverse toxicity because the host becomes tolerant to the neurotoxic effects. Much higher doses could be administered without adverse toxicity, but maximizing treatment efficacy. Our aim was to develop an innovative design for a Phase 1 study with intra patient dose escalation to induce subject tolerance. Methods: A new open label intra‐patient dose escalation method was planned. The primary objective is to determine the Maximum Tolerated Dose (MTD). DLT was defined as the occurrence of two consecutive grade 2 or 3 neuromuscular events not recovered within 24 hours at a given dose. MTD was defined as the dose where no DLT was observed among three consecutive patients, or no more than one DLT among six patients. Dosing schedule, duration and highest dose was based on the previous clinical experience. Eight possible crotoxin doses will be administered using intrapatient dose escalation, starting from 0.04 and up to 0.32 mg/m 2 . Each dose will be initially administered for 5 consecutive days with 2 days break during week‐end. Results: Determination of MTD will be as follow: the first patient will be treated up to 0.32 mg/m 2 or a lower tolerated dose. This dose is called the ith target ceiling dose (TCD i ). Next two patients will be treated up to the TCD i . →If no DLT is encountered, then TCD i is MTD. → If two or more DLT are encountered, then include 3 new patients up to the next lower dose (TCD i‐1 ) and proceed similarly. →If one DLT encountered, then add 3 more patients up to TCDi. →If no DLT is encountered among those 3 new patients, then TCDi is MTD. →If one or more DLT is encountered among those 3 new patients, then include 3 new patients up to TCD i‐1 and proceed similarly. Conclusion: host could become tolerant with some products using dose escalation and avoid toxicity. This innovative design is expected to allow fast and simple determination of MTD in these situations. The study protocol was approved by our local ethics committee and will start at early November. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B158.