p16/CDKN2A loss play a crucial role in GIST progression. Therapeutic options after progression to imatinib and sunitinib are limited. Palbociclib, an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6, was recently approved for postmenopausal women with advanced hormone receptor–positive, her2-negative breast cancer. Preclinical studies show that palbociclib inhibits the cell cycle and growth in cells with decreased p16.
This is a multicenter single-arm phase 2 clinical trial based on 2-stage Simon’s design which assesses safety and efficacy of palbociclib in patients (pts) with advanced GIST having failed at least on imatinib and sunitinib and with CDKN2A loss assessed by CGH array. All pts had to have documented progressive disease (PD) as per RECIST 1.1 before study entry. Pts receive palbocilcib 150mg day 1-day 21 (oral route), daily until PD or unacceptable toxicity. The primary endpoint is the 4-month non-PD rate according to RECIST 1.1. Based on the following hypotheses: 25% 4-month non-PD rate (H0), 45% acceptable 4-month non-PD rate (H1), 5% type I error rate, 90% power, a total of 57 assessable pts are necessary (22 for the first stage + 25 for the second stage). Following the inclusion of the first 22 pts, if ≥ 7 pts are progression-free at 4 months, the accrual will continue. In order to account for not assessable pts (+/- 10%), 63 pts will be of the French Sarcoma Group.
As of May 2017, 72 pts (52 males, 20 females) have been included in the study. Median age is 66.0 years out of the first 22 first evaluable patients had progressive disease at 4 months indicating that palbocicilib had not reached the primary endpoint to justify continuing accrual after the 1st step of the study.
Palbociclib has no significant activity as a single agent in advanced GIST with p16/CDKN2A loss. Prognostic value of CDKN2A loss in the whole population will be presented at the meeting.
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All authors have declared no conflicts of interest.