Phase I dose escalation study of the oral multi-CDK inhibitor PHA-848125

3531 Background: PHA-848125 is a novel CDK2, CDK1, CDK4 and TRKA oral inhibitor in a first in human study. PHA-848125 showed significant antitumor activity in several tumor models (including prostate, pancreas and lung). More than additive effect was observed in combination with docetaxel and bevacizumab. Methods: Phase I dose escalation study of PHA-848125 administered orally once daily for 7 days in a 2-week cycle (cy) to investigate safety and pharmacokinetics in advanced/metastatic solid tumor patients (pts). Cohorts of 3–6 pts received PHA-848125 at doses of 50 (3 pts),100 (6 pts),150 (6 pts), 200 (6 pts), 300 (1 pt) mg/day. Results: A total of 93 cys were administered to 22 pts (15 male, 7 female). The median number of cys per pt was 3 (range 1–12), with 5 pts receiving 6 cys or more. Side effects were mainly nausea/vomiting/diarrhea (max grade gr 2), tremors (max gr 3 at 200 mg/day) and ataxia (gr 3 in the 3 pts at 200 mg/day and gr 4 for the pt at 300 mg/day). Onset of ataxia was around day 4–7 of a cy and reversible in 7–8 days. Occasional mild hematological toxicity at 100 and 200 mg/day was observed and 1 pt had prolonged transaminitis at 200 mg/day. The recommended phase II dose (RP2D) was identified at 150 mg/day. At the RP2D, 6 pts received a total of 35 cys. Toxicity (mild tremors, cold sensitivity in feet/thigh/buttocks, lightheadedness, intermittent orthostatic hypotension, fatigue, neutropenia, nausea) was mild/moderate, reversible and easily manageable. PK data indicate an achievement of maximal plasma concentration at 4h (median), with a half-life of 30–40 hours. Cmax and AUC increased with the dose, with a limited variability among pts. Day 7/day 1 AUC (0–24h) ratio was ≈3. At RP2D, day 7 AUC (0–24h) was 25 μM·h (CV: 34%) and Cmax 1.47 μM. Conclusions: Overall PHA-848125 is well tolerated and tremors and ataxia are dose-limiting. The RP2D is 150 mg/day. To increase the dose and control neurotoxicity, a second schedule of 4 days on/3 days off x 3w q4w is being tested starting from 150 mg/day. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nerviano Medical Sciences Nerviano Medical Sciences Nerviano Medical Sciences Nerviano Medical Sciences