Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib
Status:
Completed
Trial end date:
2019-02-01
Target enrollment:
Participant gender:
Summary
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.