At a glance
ClinicalIndex Comparison Record- ✓Histologically confirmed GIST with c-KIT (CD117) positive staining, or KIT-negative with DOG1-positive staining or KIT/PDGFRA mutation
- ✓CDKN2A gene deletion assessed by array-CGH
- ✓Unresectable and/or metastatic disease with documented progression after 1st-line imatinib and 2nd-line sunitinib, confirmed by central review within 24 months
- ✓At least one measurable GIST lesion per RECIST v1.1
- ✕RB1 gene deletion assessed by array-CGH
- ✕Anti-cancer drugs within 5 days prior to starting PD-0332991
- ✕Concomitant cytotoxic or antineoplastic treatments (chemotherapy, immunotherapy, radiotherapy)
- ✕Another primary malignancy within 2 years (except in-situ cervical carcinoma or completely excised skin carcinoma)
Standardized by ClinicalIndex from the ClinicalTrials.gov record · verify against the source.
Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 Study
In Brief
A Phase 2 clinical trial evaluating PD 0332991 for Advanced Gastrointestinal Stromal Tumors. Completed, enrolled 29 participants across 9 sites.
Detailed 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.
Study Details
Timeline
Interventions
PD-0332991 was administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively. PD-0332991 was dosed on a flat scale of 125 mg (1 capsule x 100 mg/day, 1 capsule x25 mg/day) will be administrated orally o.d on a 21 days on / 7 days off dosing schedule. One cycle is considered to consist of 4 weeks of PD-0332991 administration. Patients should be instructed to administrate PD-0332991 with a sufficient amount of water at least 1 hour prior to a meal or at least 2 hours following a meal and to swallow the required number of capsules at approximately the same time on each day.