First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors

Abstract

Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and clinical activity. Methods Forty-seven patients were enrolled in three parts. The primary objective of Parts A and B was safety, whereas Part C evaluated the effect of proton-pump inhibitors on MK-8033 absorption. Dose escalation used an accelerated continual reassessment method, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity (except alopecia or inadequately treated nausea/vomiting/diarrhea), grade 4 hematologic toxicity (except grade 3 neutropenic fever and thrombocytopenia), or toxicity where treatment is held >3 weeks. Results Forty-six patients were treated across nine dose levels, and the MTD was 750 mg twice daily. DLTs were fatigue, nausea, vomiting, transaminitis, and hypokalemia. Most frequent toxicities were fatigue (28.3%), nausea (21.7%), and alopecia (19.6%), predominately grade ≤ 2. One patient with endometriod adenocarcinoma achieved a partial response and eight had stable disease. Median progression-free survival (PFS) was 57 days. Strikingly, the PFS for the one responder was 846 days. PK results showed that proton-pump inhibitors have no effect on MK-8033 absorption. Conclusion MK-8033 was well tolerated with no significant toxicity issues, albeit with limited clinical activity. Unfortunately, the company decided to discontinue further clinical development of MK-8033.

Keywords: C-met inhibitor; First-in-human phase I study; Mk-8033; Solid tumor.

Figures

Fig. 1

Mean plasma concentration profiles over the 50 to 1500 mg twice daily doses of MK-8033. Peak concentrations on Day 1 and 14 appeared to occur between 1 and 3 h across the dose range; however, this analysis was not conclusive due to the large inter-subject variability and the small number of samples at each time point (see Note). Note: For the 200 mg dose, n = 2 for Day 8 predose, Day 14 12 h, and Day 14 72 h time points; For the 400 mg dose, n = 3 for Day 4 predose and Day 14 12 h and 72 h, and n = 2 for Day 14 28 h time points. For the 550 mg dose, n = 6 for Day 1 2 h, Day 4 predose, and all Day 14 time points, and n = 5 for Day 14 24 h and 72 h time points. For the 750 mg dose, n = 3 for Day 1 3 h time point. For the 1050 mg dose, n = 4 for Day 8 and Day 14 time points. Lastly, for the 1500 mg dose, n = 1 for Day 14 time points

Fig. 2

Individual steady state plasma concentration profiles following administration of twice daily oral doses of 770 mg MK-8033 alone or in combination with one daily 20 mg omeprazole for the two patients who completed the cross-over study (inset = semilog scale). Based on these data, the proton-pump inhibitor omeprazole does not appear to strongly impact the steady state pharmacokinetics of MK-8033