Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib (CYCLIGIST)
|ClinicalTrials.gov Identifier: NCT01907607|
Recruitment Status : Active, not recruiting
First Posted : July 25, 2013
Last Update Posted : October 2, 2017
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.
Exploratory, one-arm, multicenter, phase II clinical trial based on twostage Simon's design
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.
This is a multicentre single-arm Phase II study evaluating the efficacy and safety of orally PD-0332991, 125 mg/day, 21 days on/7 days off, in patients with documented disease progression while on therapy with 2nd line sunitinib for unresectable and/or metastatic GIST. Indeed, the usual treatment for advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib is best supportive care for which outcome data are already available (Demetri et al., 2012; Italiano et al., 2012). Sixty three patients will be included in 10 centres of the French Sarcoma Group over a period of 18 months of enrolment.
Patients will be evaluated at scheduled visits in up to three study periods:
- Pre-treatment (PRE TT): from signature of informed consent to the first treatment by PD-0332991.
- Treatment (TT): from the first treatment by PD-0332991 to the first 28 days following the last PD-0332991 administration.
- Follow-up (FUP): after treatment discontinuation, all patients must be followed up for 28 days after the last dose of the study drug for safety assessment (AEs and/or SAEs).
|Condition or disease||Intervention/treatment||Phase|
|Advanced Gastrointestinal Stromal Tumors||Drug: PD-0332991 will be administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively.||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||63 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 Study|
|Study Start Date :||August 2013|
|Estimated Primary Completion Date :||April 2018|
|Estimated Study Completion Date :||April 2019|
Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib.
PD-0332991 is formulated as gelatin capsules of 100 mg and 25 mg respectively.
Drug: PD-0332991 will be administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively.
PD-0332991 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.
- Efficacy assessment of PD-0332991 [ Time Frame: 16 weeks ]Efficacy is assessed based on 4-month non progression. Non progression is defined as complete or partial response (CR, PR) or stable disease (SD), using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Non-progression rate will be calculated as the number of alive and progression free patients divided by the number of eligible and assessable patients for the efficacy analysis. Eligible and assessable populations are described in corresponding section of protocol. As recommended by RECIST v1.1, all claimed response will be centrally reviewed by an expert of the study. The results of the centralized radiological review will be used for the analysis of the primary endpoint.
- Objective response [ Time Frame: 16 weeks ]Objective response is defined as complete response (CR) or partial response (PR) according to RECIST v1.1
- Progression-free survival [ Time Frame: 16 weeks ]Progression-free survival is defined as the time from the first administration of treatment to progression (as per RECIST v1.1) or death of any cause, whichever occurs first
- Overall survival [ Time Frame: 16 weeks ]Overall survival is defined as the time from the first administration of treatment to death.
- Progression [ Time Frame: 16 weeks ]Progression will also be assessed using CHOI criteria
- Safety of PD-0332991 [ Time Frame: 16 weeks ]Safety of PD-0332991 will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE), v4.0
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01907607
|Bordeaux, Gironde, France, 33076|
|Centre Georges-Francois Leclerc|
|Dijon, France, 21079|
|Centre Oscar Lambret|
|Lille, France, 59020|
|Centre Léon Bérard|
|Lyon, France, 69373|
|Hôpital de la Timone - AP-HM|
|Marseille, France, 13385|
|Centre René Gauducheau|
|Nantes, France, 44805|
|Hôpital Saint-Antoine (AP-HP)|
|Paris, France, 75571|
|CHU de REIMS - Hôpital Robert Debré|
|Reims, France, 51092|
|Institut Gustave Roussy|
|Villejuif, France, 94800|