Advanced Gastrointestinal Stromal Tumors Clinical Trial
Official title:
Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 Study
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.
Medical Conditions : Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib Study design : Exploratory, one-arm, multicenter, phase II clinical trial based on two-stage Simon's design Main objective : 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. Secondary objectives - To assess the antitumor activity of PD-0332991 in terms of : - Objective response rate (ORR) (as per RECIST v1.1 criteria) - Progression-free survival (PFS) (as per RECIST v1.1 criteria) - Overall survival - To assess the safety of PD-0332991 Study drug formulation: PD-0332991 is formulated as gelatin capsules of 100 mg and 25 mg respectively. PD-0332991 was administrated orally. PD-0332991 dosed on a flat scale of 125 mg. PD-0332991 was administrated on a 21 days on / 7 days off dosing schedule. One cycle was considered to consist of 4 weeks of PD-0332991 administration.Patients were treated with PD-0332991 until progression of disease, unacceptable toxicity, death or discontinuation for any other reason. Tumor assessment and response assessed according to RECIST v1.1, with same type of exam in regard of baseline. All potential sites of tumor lesions (target and non-target lesions) assessed using MRI or CT Scan with IV contrast of the Thorax Abdomen and Pelvis using a 5mm slice thickness with a contiguous reconstruction algorithm (a PET scan is not acceptable for radiological evaluation). Evaluation were assessed: - at baseline within 21 days before the first dose of PD-0332991 - at D(28) of Cycle 1, at D(28) of Cycle 2 then every 8 weeks until month six and then every 12 weeks until disease progression or starting other treatment. Response regarding the first endpoint was assessed by central radiology review. Whenever the criteria of response are met (Complete Response (CR) or Partial Response (PR)), the appropriate imaging tests were repeated at least four weeks later in order to confirm the response. The decision regarding patient management remained with the local investigator. optionnal: Fresh tumor biopsies FFPE (Formalin-Fixed Paraffin-Embedded) at screening and at Day 21 of Cycle 1 are encouraged to be collected. Once collected, the samples may be profiled by IHC, and array gene expression analysis ;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00940563 -
A Prospective, Multicenter Study on Best Clinical Use of Imatinib in the Advanced Gastrointestinal Stromal Tumors
|
Phase 2 | |
| Recruiting |
NCT05208047 -
(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
|
Phase 3 |