The treatment of advanced GIST patients is based on imatinib followed with sunitinib in case of resistance/intolerance. However, the median progression-free survival (PFS) on sunitinib is frequently short, and after failure with both imatinib and sunitinib, treatment remains controversial. Previous studies on GISTs have linked 9p21 alterations to tumor progression (El-Rifai et al. 2000; Kim et al., 2000; Schneider-Stock et al., 2003; Schneider-Stock et al., 2005; Romeo et al. 2009; Haller et al., 2008) but the driver gene was not positively identified (CDKN2A, CDKN2B, or MTAP) (Astolfi et al., 2010; Belinsky et al., 2009; Perrone et al., 2005; Assamaki et al. 2007; Huang et al., 2009). A recent study has shown that homozygous 9p21 deletions target CDKN2A and more specifically p16INK4a 4. Most of the CINSARC genes are known to be under the transcriptional control of E2F. RB1 sequesters E2F, which is released from the complex upon RB1 phosphorylation by CDK4. CDK4 is, in turn, inhibited by p16INK4a. Hence, we hypothesize that alteration of the restriction point via deletion of p16INK4a (and more rarely of RB1: 20% of cases) gene in GISTs is likely to be a causative event that leads to the overexpression of CINSARC genes, which in turn induce chromosome instability and ultimately metastasis. Low p16INK4a expression was associated with response to PD-0332991 in several in vitro tumor model(Konecny et al. 2011; Katsumi et al. 2011; Finn et al. 2009). Considering our molecular data, we believed that PD-0332991 warrants clinical investigation in advanced gastrointestinal stromal tumors with alteration of p16INK4a. This alteration is detectable by comparative genomic hybridization which is a technique highly manageable in the context of routine clinical care and clinical trial. Main objective was to assess the antitumor activity of PD-0332991 in terms of non-progression at 16 weeks (after centralized review) in patients with documented disease progression while on therapy with imatinib and sunitinib for unresectable and/or metastatic GIST.
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Number of Participants With Non Progression at 4 Months
Timeframe: 16 weeks after first administration of treatment