A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM

Abstract

3016 Background: Some GIST patients with response to IM develop resistance to IM. A favorable kinase inhibition profile of PKC (KIT, PDGFR-1,-2, VEGFR-2) and synergistic IM in vitro data provided the rationale for this non-randomized, open label study. Methods: Pts with metastatic GIST were eligible if they progressed after ≥4 months on IM therapy, including at least 2 months at ≥600mg/d. Drug administration and PK schedules were designed to assess the safety and tolerability of the combination, as well as the PK interaction between IM and PKC. Results: Nineteen patients have been entered so far at doses ranging from IM 600 to 1000mg/d in combination with PKC 200mg/d. Frequently reported CTC Gr 1–2 adverse events in this heavily pretreated group of patients included nausea, vomiting, anorexia, diarrhea, edema, fatigue, dyspepsia, candidiasis, sweating, skin toxicity and anemia. Four Grade 3 AEs were attributed to the investigational combination: hyperglycemia, transient asymptomatic hyperamylasemia, hypercalcemia and transaminitis, all reported previously for PKC alone. Notably, hyperthyroidism manifested by elevated TSH (grade 2, manageable) was seen in 4/12 patients. Complete PK data for the first twelve patients treated with PKC 100 mg b.i.d. in combination with IM 600mg q.d. from 2 to 5 months show that PKC trough plasma concentrations increased ∼2-fold over that seen in AML studies with PKC alone, even taking into account the expected decrease in the PKC plasma concentration of ∼75% by day 28 seen in previous AML studies with PKC. IM exposure decreased ∼70% after one month of co-administration with PKC, either due to enzyme induction or protein binding interactions. The study was therefore amended to allow for inter-cohort dose escalation of IM and temporary dose reduction of PKC to decrease peak levels which resulted in reduced toxicity and increased IM PK trough levels equal to 600 mg IM. 2/5 patients evaluable for response had stable disease at 4 months, with characteristic CT findings. Conclusion: Preliminary evidence in this study indicates activity of the combination of PKC412 and IM in IM-resistant GIST. This study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis