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    Summary
    EudraCT Number:2013-000283-28
    Sponsor's Protocol Code Number:IB_2013–01
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-16
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2013-000283-28
    A.3Full title of the trial
    Efficacy and Safety of PD-0332991 in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 study
    Efficacité et tolérance du PD-0332991 chez les patients atteints d’une Tumeur Stromale Gastro Intestinale (GIST) localement avancée et réfractaire à Imatinib et Sunitinib : une étude de phase 2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    _
    A.3.2Name or abbreviated title of the trial where available
    CYCLIGIST
    A.4.1Sponsor's protocol code numberIB_2013–01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInstitut Bergonié
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportINCA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUNICANCER
    B.5.2Functional name of contact pointClaire Jouffroy
    B.5.3 Address:
    B.5.3.1Street Address101, rue de tolbiac
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75013
    B.5.3.4CountryFrance
    B.5.4Telephone number01.71.93.63.66
    B.5.5Fax number01.53.79.02.90
    B.5.6E-mailc.jouffroy@unicancer.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PD-0332991
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10062427
    E.1.2Term Gastrointestinal stromal tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    Evaluer l’efficacité du PD-0332991 en termes de non progression à 16 semaines chez des patients atteints d’une Tumeur Stromale Gastro Intestinale (GIST) non résécable et/ou métastatique et en progression lors d’un traitement par imatinib et sunitinib.
    E.2.2Secondary objectives of the trial
    To assess the antitumor activity of PD-0332991 in terms of :
    -Objective response rate (ORR) (as per RECIST v1.1 criteria Appendix 3)
    -Progression-free survival (PFS) (as per RECIST v1.1 criteria Appendix 3)
    -Non progression rate and ORR assessed using CHOI criteria (Appendix 4 )
    -Overall survival
    To assess correlation between ORR-RECIST and ORR- CHOI
    To assess the safety of PD-0332991: Incidence of adverse events (AEs), seriousadverse events (SAEs) and abnormal laboratory results (hematology, blood
    chemistry) will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE), v4.0. (Appendix 4)
    To assess the pharmacodynamic (PD) effect of PD-0332991 on gene expression profile in patient consenting to research biopsies (Optional study) before starting treatment and on treatment.
    Evaluer l'activité anti-tumorale du PD-0332991 en termes de:
    -Taux de réponse objective (ORR) (selon les critères RECIST v1.1)
    -Survie sans progression (PFS) (selon les critères RECIST v1.1)
    -Taux de non progression et ORR évalués selon les critères CHOI
    -Survie globale
    Evaluer la corrélation entre ORR-RECIST et ORR-CHOI
    Evaluer la tolérance du PD-0332991: Incidence des Evénements Indésirables (EI), Evénements Indésirables Graves (EIG) et résultats de laboratoire anormaux (hématologie, biochimie sanguine) qui seront évalués par la CTCAE v4.0 (Common Terminology Criteria for Adverse Events)
    Evaluer l’effet pharmacodynamique (PD) du PD-0332991 sur le profil d'expression génique du patient consentant à des biopsies de recherche (étude optionnelle) avant de commencer le traitement et pendant le traitement.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Des biopsies tumorales (en option) au screening et au jour 21 du Cycle 1 peuvent être collectées. Une fois prélevés, les échantillons peuvent être analysés par IHC et une analyse de l'expression génique peut être réalisée pour identifier l'activité pharmacodynamique du PD-0332991 chez les patients atteints de GIST.
    Comme il s'agit d'un domaine de recherche actif, plusieurs biomarqueurs peuvent être analysés s’ils sont justifiés par les résultats des activités de recherche internes ou externes.
    Chaque échantillon sera envoyé au promoteur.
    E.3Principal inclusion criteria
    1. Male or female patients ≥ 18 years of age
    2. 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
    3. CDKN2A gene deletion assessed by array-comparative genomic hybridization (array-CGH)
    4. Unresectable and/or metastatic disease with documented progression according to modified RECIST criteria (see section 7.2.1.5 of protocol) after 1st line imatinib and 2nd line sunitinib. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical (CT scans or MRI) obtained at less from 4 months interval within the 24 months before inclusion.
    5. 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.
    6. A performance status of 0, 1 or 2 according to the Eastern Cooperative Oncology Group (ECOG) scale(Appendix 1)
    7. Recovery from Grade 2 to 4 toxicity related to prior line of treatment assessed according to NCICTCAE v.4.0 (Appendix 2)
    8. 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
    9. Adequate liver function as shown by:
    · Serum or plasma ALT and AST ≤ 3.0 x ULN (regardless of the presence or absence of metastases)
    · Serum or plasma total bilirubin: ≤ 1.5 x ULN (excepted for patients with Gilbert’s syndrome)
    10. Adequate renal function as shown by serum creatinine ≤ 2 x ULN
    11. Patients who give a written informed consent obtained according to French and European regulations.
    12. Patients affiliated to the French Social Security
    E.4Principal exclusion criteria
    1. RB1 gene deletion assessed by array-comparative genomic hybridization (array-CGH)
    2. Patients who received anti-cancer drugs ≤ 5 days prior to starting PD-0332991
    3. 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
    4. 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
    5. Patients with a corrected QT interval using Bazett’s formula (QTcB) > 470 msec.
    6. 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)
    7. Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PD-0332991 (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
    malabsorption syndrome, or extensive (>1m) small bowel resection, inability to swallow oral medications). Prior partial gastrectomy is not an exclusion criterion.
    8. Patients with prior complete gastrectomy
    9. 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.
    10. 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
    11. Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory
    12. 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
    13. Pregnant or breast-feeding women
    14. Women of child-bearing potential not employing two effective methods of birth control. Effective contraception must be used throughout the trial and 24 weeks after the end of PD-0332991 (e.g. condom with
    spermicidal jelly, foam suppository or film; diaphragm with spermicide; male condom and diaphragm with spermicide, oral, implantable, or injectable contraceptives). Women of child-bearing potential defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive
    months (i.e. who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 21 days prior to starting study drug.
    15. Fertile males not willing to use contraception as stated above
    16. Patients unwilling or unable to comply with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    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 (RECISTv1.1). 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.
    E.5.2Secondary end point(s)
    -Objective response is defined as complete response (CR) or partial response (PR) according to RECIST v1.1.
    -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 is defined as the time from the first administration of treatment to death.
    - Progression will also be assessed using CHOI criteria
    - Safety of PD-0332991 will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE), v4.0
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 63
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state63
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-11-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-02-07
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