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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
Tibes et al. (Tue,) studied this question.