A dose-escalation phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 28 days on/14 days off schedule.
3046 Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1, 2, 4, 7, and 9 in the low nanomolar range. A phase I dose escalation multicenter study was initiated to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with advanced solid tumors. Methods: BAY was administered twice daily as an oral solution on a 28 days on / 14 days off schedule (cycle length 42 days, 3+3 design). PK was evaluated on cycle 1 day 1, 2, and 15. Response rate was assessed according to RECIST 1.1. Results: Ten pts were treated at doses of 0.6 (4 pts) and 1.0 (6 pts) mg per day. Tumor types included 3 non-small cell lung, 2 colorectal, 2 melanoma and 3 others. CTCAEv4 grade 1/2 drug related adverse events (AEs) occurring in more than 3 patients were nausea (5 pts), hot flashes (4), vomiting, diarrhea, dyspepsia, and fatigue (3). The median interval between start of treatment and occurrence of hot flashes was 23 days. Drug-related grade 3 AEs were hyponatremia (2 pts) and edema, lymphopenia, myalgia, fatigue, and hypokalemia in 1 pt each. Hyponatremia in one and hypokalemia in another patient were dose limiting toxicities in cohort 2. Enrollment has been stopped. BAY PK was dose proportional and T1/2 was 13 hours; major metabolite levels were low. One pt with metastatic malignant melanoma pretreated with interferon, talimogene laherparepvec, and ipilimumab (best prior response: progressive disease) achieved stable disease (SD) lasting for 5 months. Three pts had SD lasting for 2.5 - 3 months (thyroid, colorectal, squamous esophageal). Conclusions: BAY administered for 28 days on / 14 days off demonstrated a limited tolerability. This is in contrast to the ongoing 3 days on / 4 days off trial which is currently at a dose level of 20 mg per day. Hot flashes were an infrequent AE in the other dosing schedule but occurred in 4 of the 10 pts presented here. The long interval between start of treatment and occurrence of hot flashes suggests that the 28 days of continuous treatment contributed to the lower tolerability observed in this trial. The 3 days on / 4 days off schedule will be used in the further clinical development of BAY.