Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib

NCT01907607 | Completed Phase 2 Results DMC

• 1 other identifier: IB 2013-01
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 9

Brief 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.

Conditions

Advanced Gastrointestinal Stromal Tumors

Keywords

Gastrointestinal Stromal Tumor; PD-0332991; Efficacy; advanced; safety

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Non Progression at 4 Months

  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.

  16 weeks after first administration of treatment

Secondary Outcomes (3)

• Number of Participants With Objective Response at 4 Months

  16 weeks after first administration of treatment

• Efficacy Assessment of PD-0332991 in Terms of Progression-free Survival Time

  up to 18 months following first administration of treatment

• Efficacy Assessment of PD-0332991 in Terms of Overall Survival Time

  up to 24 months following first administration of treatment

Study Arms (1)

PD-0332991

EXPERIMENTAL

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

Interventions

PD 0332991 DRUG

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.

PD-0332991

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥ 18 years of age
• Histologically confirmed GIST of any anatomical location and confirmed by the RRePS Network ; positive immunohistochemical staining for c-KIT (CD117); or negative staining for KIT, but with either positive staining for DOG1 or an identified mutation of KIT or PDGFRA gene
• CDKN2A gene deletion assessed by array-comparative genomic hybridization (array-CGH)
• At least one measurable GIST lesion according to RECIST (v1.1 Appendix 3). A previously irradiated lesion is eligible to be considered as a measurable lesion provided that there is objective evidence of progression of the lesion prior to starting PD-0332991.
• A performance status of 0, 1 or 2 according to the Eastern Cooperative Oncology Group (ECOG) scale(Appendix 1)
• Recovery from Grade 2 to 4 toxicity related to prior line of treatment assessed according to NCICTCAE v.4.0 (Appendix 2)
• Adequate bone marrow function as shown by:
• Blood absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Blood platelets ≥ 100 x 109/L
• Blood hemoglobin (Hgb) \> 9 g/dL
• Adequate liver function as shown by:
• c. Serum or plasma ALT and AST ≤ 3.0 x ULN (regardless of the presence or absence of metastases) d. Serum or plasma total bilirubin: ≤ 1.5 x ULN (excepted for patients with Gilbert's syndrome)
• Adequate renal function as shown by serum creatinine ≤ 2 x ULN
• Patients who give a written informed consent obtained according to French and European regulations.
• Patients affiliated to the French Social Security

You may not qualify if:

• RB1 gene deletion assessed by array-comparative genomic hybridization (array-CGH)
• Patients who received anti-cancer drugs ≤ 5 days prior to starting PD-0332991
• Patients who are treated or planned to be treated concomitantly with other cytotoxic or antineoplastic treatments, such as chemotherapy, immunotherapy, biological response modifiers, or radiotherapy
• Patients with another primary malignancy within 2 years prior to starting the study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, or completely excised (R0 resection) basal or squamous cell carcinoma of the skin
• Patients with a corrected QT interval using Bazett's formula (QTcB) \> 470 msec.
• Current use or anticipated need for food or drugs that are known strong cytochrome P450 (CYP)3A4 inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, tilithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and delaviridine)
• Patients with prior complete gastrectomy
• Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
• Patients with any clinically significant medical or surgical condition which, according to investigators' discretion, should preclude participation
• i.e. active or uncontrolled infection, uncontrolled diabetes, active or chronic liver disease (cirrhosis, chronic active hepatitis or chronic persistent hepatitis)
• hepatitis B or C virus carriers with normal liver function tests, can be included
• Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory
• Patients who are currently receiving anticoagulation treatment with therapeutic doses :
• of warfarin or equivalent anticoagulant (e.g. high dose aspirin or clopidogrel or other)
• or have an INR \>1.5. Treatment with acetylsalicyclic acid 100 mg daily or low molecular weight heparin (LMWH) is allowed

Sponsors & Collaborators

• Institut Bergonié: lead

Study Sites (9)

Institut Bergonié

Bordeaux, Gironde, 33076, France

Location

Centre Georges-Francois Leclerc

Dijon, 21079, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

Hôpital de la Timone - AP-HM

Marseille, 13385, France

Location

Centre René Gauducheau

Nantes, 44805, France

Location

Hôpital Saint-Antoine (AP-HP)

Paris, 75571, France

Location

CHU de REIMS - Hôpital Robert Debré

Reims, 51092, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Related Publications (1)

• Toulmonde M, Blay JY, Bouche O, Mir O, Penel N, Isambert N, Duffaud F, Bompas E, Esnaud T, Boidot R, Geneste D, Ghiringhelli F, Lucchesi C, Bellera CA, Le Loarer F, Italiano A. Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study. Clin Cancer Res. 2019 Aug 1;25(15):4611-4615. doi: 10.1158/1078-0432.CCR-18-3127. Epub 2019 Apr 12.

  PMID: 30979737 RESULT

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Results Point of Contact

• Title: Pr Antoine Italiano
• Organization: Institut Bergonié

a.italiano@bordeaux.unicancer.fr

33 5 56 33 33 33

Study Officials

• Antoine Italiano, MD/PhD

  Institut Bergonié

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2013
• First Posted: July 25, 2013
• Study Start: February 1, 2014
• Primary Completion: December 1, 2016
• Study Completion: February 1, 2019
• Last Updated: August 24, 2025
• Results First Posted: January 20, 2021

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (9)