Androgen receptor (AR) inhibition can upregulate c-MET expression which can drive CRPC progression. We have previously described the safety and toxicity profile of concurrent treatment with enza and crizo, a potent c-MET inhibitor in a phase 1 study. Since crizo is a substrate for CYP3A4, which is strongly induced by enza, we performed a PK analysis to evaluate its impact on steady state crizo levels.
A 3 + 3 dose escalation design was employed to test increasing doses of crizo at 250mg daily (dose level 1; n = 3), 200 mg BID (dose level 2; n = 6) and 250mg BID (dose level 3; n = 15) in combination with a fixed dose of enza 160 mg daily in 28 day cycles. PK samples drawn during cycle 2 were used to estimate steady state PK parameters including peak (Cmaxss) and trough (Cminss) plasma concentration and area under the curve over a dosing interval (AUCτss), reported as the geometric mean ± SD.
The crizo Cminss increased progressively across dose levels from 20.7 ± 1.8 ng/mL (250 mg QD) to 70.2 ± 36.4 ng/mL (250 mg BID). Among the 12 patients enrolled on dose level 3 with available PK data, the crizo Cmaxss and AUCτss were 104 ± 45 ng/mL and 1,000 ± 476 ng-h/mL respectively. This represents a 73.8% decrease in crizo steady state exposure compared to a historical data for NSCLC patients with normal renal function treated with crizo monotherapy at 250 mg BID (Cminss: 285.0 ng/mL; Cmaxss: 315 ng/mL and AUCτss: 3,817 ng-h/mL; Tan et al Inv. New Drugs 2016). Enza Cminss was similar across the crizo dose levels (250mg QD: 10.6 ± 4.6 μg/mL; 250mg BID: 12.5 ± 3.2 μg/mL) and was in excellent agreement with previously reported steady state levels in the phase 3 AFFIRM trial (11.7 ± 2.9μg/mL; Gibbons et al Clin Pharmacokinetics 2015).
Concurrent administration of enza resulted in a clinically significant ∼74% increase in the apparent oral clearance of crizo suggestive of a clinically significant PK drug interaction. Further investigation into the optimal combination of c-MET inhibitors with novel AR inhibitors is required. Our results highlight the importance of considering PK interactions when evaluating novel combination strategies in CRPC.
Clinical trial identification
Legal entity responsible for the study
Dana-Farber Cancer Institute.
Astellas Pharma Inc.
K.P. Gray: Stock ownership: DVAX M-E. Taplin: Research funding, Advisory board, Honorarium: Medivation/Pfizer. A.D. Choudhury: Honoraria: Bayer, Astellas Australia, Janssen Latin America; Research funding: Bayer (pending). M. Pomerantz: Advisory Board/committee: NCI/PDQ; Speakers bureau: Astellas, APACE, MD Anderson, PCF. J. Bellmunt: Advisory role: Genentech, MSD, Pfizer, GSK, BMS, Pierre-Fabre, Sanofi Aventis, Astellas, OncoGenex, Janssen; Lectures fee: Pfizer, MSD, GSK, Novartis, Pierre-Fabre, Astellas; Research funding: Takeda, Pfizer, Novartis, Sanofi Aventis. C. Yu: Employee: Daiichi Sankyo, Inc. S. Srinivas: Advisory board; Research funding: Exelexis DSMC: Pfizer P.W. Kantoff: Scientific Advisory board; BIND Biosciences, Inc., BN Immunotherapeutics. Context Therapeutics LLC, DRGT, GE Healthcare, Janssen, Metamark (-no longer in business), New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics (previously Blend), Thermo Fisher; Investment interests: Context Therapeutics, DRGT, placon, Seer, Tarveda therapeutics. C. Sweeney: Stock or Other ownership: Leuchemix Consulting; Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech, AstraZeneca, Pfizer, Tolmar; Research funding: Janssen Biotech (Inst), Astellas Pharma (Inst), Sanofi (Inst), Bayer (Inst), Sotio (Inst) Patents, royalties; Other Intellectual Property: Leuchemix: Parthenolide, dimethylaminoparthenolide; Exelixis: Abiraterone plus cabozantinib combination L.C. Harshman: Advisory role: Bayer, Genentech, Dendreon, Pfizer, Medivation/Astellas, Kew Group, Theragene, Corvus, Merck, Exelixis, Novartis; Research institution: Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer. All other authors have declared no conflicts of interest.