GEM231 is a mixed-backbone
oligonucleotide targeting the regulatory subunit alpha of type I
protein kinase A, which plays an important role in growth and maintenance of
malignancies. Preclinically,
GEM231 inhibited human
cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of
GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid
tumors. Fourteen patients (13 evaluable for safety) received escalating doses of
GEM231 at 20-360 mg/m2 (2.5-9 mg/kg).
Tumor histologies included
non-small cell lung cancer,
renal cell cancer,
sarcoma, and others. The plasma pharmacokinetics of
GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II
fever and
fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or
thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline
thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible
transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with
colon cancer had stabilization of a previously rising
carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone
oligonucleotide in
cancer patients, high plasma concentrations of
GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week
treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the
duration of therapy at the highest
GEM231 dose tested.