A phase I trial of an anti-pka oligonucleotide (GEM231) administered with weekly CPT-11

2074 Background: PKA RIa is a primary mediator of cAMP activity and is upregulated in many cancers. GEM231 (G) is a 2nd generation RNA/DNA oligonucleotide targeting the PKA regulatory subunit (RIa). Preclinically, G has synergistic antitumor effects when combined with irinotecan (IRI). Methods: This study evaluated the safety, PK, and biological profile of IRI combined with. Initially IRI was administered at 85 mg/m2 q wk X 4 along with G (40, 80 or 120 mg/m2/d for 5d X 4 wks) followed by a 2 wk rest. Due to DLTs (see table) in initial cohorts, the protocol was amended to administer full dose IRI (125 mg/m2) with a lower dose of G (20 mg/m2/day x 5) by a 2 wk on 1 wk off schedule. Additional PK sampling (@ 48 hrs) was added to evaluate the potential for altered SN-38 clearance by G, as found in preclinical models. Extracellular PKA (ECPKA) is measured in plasma at baseline and weekly thereafter. Results: 19 patients were enrolled on the original protocol, and 3 patients have received treatment on the amen...