Ignite Creation Date:
2024-05-06 @ 1:49 AM
Last Modification Date:
2024-10-26 @ 11:10 AM
Study NCT ID:
NCT01907607
Status:
COMPLETED
Last Update Posted:
2021-01-20
First Post:
2013-07-22
Brief Title:
Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib
Sponsor:
Institut Bergonié
Organization:
Institut Bergonié
Study Overview
Official Title:
Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib A Phase 2 Study
Status:
COMPLETED
Status Verified Date:
2020-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CYCLIGIST
Brief Summary:
The treatment of advanced GIST patients is based on imatinib followed with sunitinib in case of resistanceintolerance 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 modelKonecny 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 andor metastatic GIST
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 modelKonecny 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 andor metastatic GIST
Detailed Description:
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 Simons 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 andor metastatic GIST
Secondary objectives
To assess the antitumor activity of PD-0332991 in terms of
Objective response rate ORR as per RECIST v11 criteria
Progression-free survival PFS as per RECIST v11 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 administrationPatients 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 v11 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 D28 of Cycle 1 at D28 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 design Exploratory one-arm multicenter phase II clinical trial based on two-stage Simons 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 andor metastatic GIST
Secondary objectives
To assess the antitumor activity of PD-0332991 in terms of
Objective response rate ORR as per RECIST v11 criteria
Progression-free survival PFS as per RECIST v11 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 administrationPatients 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 v11 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 D28 of Cycle 1 at D28 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None