Phase 1 Study Of Andes-1537: A Novel Antisense Oligonucleotide Against Non-Coding Mitochondrial Dna In Advanced Solid Tumors.

2557 Background: New non-coding RNAs, which appear to be involved in cell proliferation in animal cells, have been discovered by L.Burzio and co-workers. Andes-1537 is a short single stranded phosphorothioate-deoxyoligonucleotide which binds by base pairing to one of these newly discovered non-coding RNAs, named Antisense non-coding mitochondrial RNA (ASncmtRNA). The resulting RNA-DNA hybrid is then hydrolyzed by two cellular RNases: RNase H and DICER resulting in microRNAs. In vitro experiments with cells have shown Andes-1537 affects cancer cells by: a) inducing apoptosis by lowering the expression of anti-apoptotic proteins such as survivin b) decreasing proliferative signaling through inhibition of the expression of proteins such as cyclin D1 and cyclin B1, and c) inhibition of tissue invasion/metastatic proteins such as n-cadherin, B-catenin and metastasis inducing factors. Methods: The safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) characteristics and efficacy of Andes -1537 was assessed in a phase 1 study. Patients with all solid tumors were enrolled in 5 cohorts at 100 mg subcutaneous (SC), 200 mg SC, 400 mg SC, 600 mg SC and 800 mg SC twice weekly. Results: 22 patients (14 M: 8F) with heavily pretreated solid tumors were enrolled in 5 cohorts. Two dose-limiting toxicities occurred at the 800 mg dose level both of which were injection site reactions: one precluding full cycle 1 dose delivery, and one involving grade 3 skin necrosis due to vascular occlusion and inflammation. No other grade 3/4 toxicities were seen. Grade 2 toxicities including injection site reactions and erythema. The MTD has been determined to be 600 mg SC twice weekly. Two patients (one with pancreatic cancer and one with cholangiocarcinoma) had stable disease on scans beyond six months. No partial or complete responses were seen with Andes 1537. PK data reveals a linear PK profile. Conclusions: Andes-1537 is a well-tolerated drug with a novel mechanism. It was determined to be tolerable at 600 mg SC twice weekly. An efficacy signal in pancreatic cancer and cholangiocarcinoma was seen at 200 mg dose level and thus dose expansion is under consideration. Clinical trial information: NCT02508441.