Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib (CYCLIGIST)
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|ClinicalTrials.gov Identifier: NCT01907607|
Recruitment Status : Completed
First Posted : July 25, 2013
Results First Posted : January 20, 2021
Last Update Posted : January 20, 2021
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.
|Condition or disease||Intervention/treatment||Phase|
|Advanced Gastrointestinal Stromal Tumors||Drug: PD 0332991||Phase 2|
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.
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
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||29 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|
|Actual Study Start Date :||February 2014|
|Actual Primary Completion Date :||December 2016|
|Actual Study Completion Date :||February 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
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.
- Number of Participants With Non Progression at 4 Months [ Time Frame: 16 weeks after first administration of treatment ]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.
- Number of Participants With Objective Response at 4 Months [ Time Frame: 16 weeks after first administration of treatment ]Objective response is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 Efficacy is assessed based on objective response at 4-month. Objective response is defined as complete or partial response (CR, PR) using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Objective reponse will be calculated as the number of alive patients with objective reponse 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.
- Efficacy Assessment of PD-0332991 in Terms of Progression-free Survival Time [ Time Frame: up to 18 months following first administration of treatment ]
Progression-free survival time 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.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
- Efficacy Assessment of PD-0332991 in Terms of Overall Survival Time [ Time Frame: up to 24 months following first administration of treatment ]Overall survival is defined as the time from the first administration of treatment to death.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
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|
|Principal Investigator:||Antoine Italiano, MD/PhD||Institut Bergonié|