Ignacio Garrido-Laguna, MD at Huntsman Cancer Institute discusses the ASCO 2020 abstract entitled A phase I, first-in-human, open-label, dose"‘escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP"‘3654 administered daily for 28 days to patients with advanced solid tumors.
Context:
TP-3654 is an oral, second-generation, active PIM-1 kinase inhibitor with PIM 2 , 3 activity and positive selectivity against other kinases. These cytoplasmic serine / threonine kinases are highly expressed in many cancers, and their oncogenic ability was primarily due to suppressing downstream apoptosis of stimuli including inflammatory cytokines and other immune effectors. It has also been shown that TP-3654 mediates different aspects of the tumor microenvironment in different hematologic and solid tumor models that induce stromal Pim-1. Thus, Pim kinases are desirable targets for treating certain malignancies in humans.
Approaches:
The first individual, multicenter, phase 1 dose escalation study to investigate the protection and clinical behavior of TP-3654 in patients with advanced solid tumors using a conventional 3 + 3 configuration with a changed Fibonacci scheme.
Reviews:
Ten patients received 480, 720, and 1080 mg respectively, between 30Apr and 31Dec2019. Grade 3 AEs were infection with scrotum wound, altered mental state, anemia, collapse, and lower extremity edema, none were linked to drug research and all were manageable with supportive treatment. No Grade 4 or 5 AEs, and no DLTs were present. The median SD period was 5.5 months (6/10) and > 16wks (4/10) for extended SD. There was a 22 percent reduction in tumor volume (SD > 5 + mos) in one CRC patient with 4 lines of previous therapy. Throughout all 3 cohorts, the TP-3654 plasma PK values (Cmax, AUC) continuously increased. 195, 1965 (480 mg); 357, 3310 (720 mg); 735, 6922 (1080 mg), respectively, were typical Cmax (ng / mL) and AUC0-24 (ng*hours / mL). With higher doses, PK values increased linearly without saturation being reached. Mononuclear peripheral blood cells were separated from subjects prior to treatment and up to 24 hours after treatment. Western blotting from protein lysates showed a decline in BAD and p70s6 K protein phosphorylation, both regulated by PIM-1 kinase.
Findings:
These findings indicate that in patients with heavily pretreated, relapsed, and resistant solid tumors, TP-3654 is tolerated as a monotherapy which warrants further clinical development in selected indications.