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Safety and Efficacy of Exemestane Plus Dasatinib Versus Placebo for Advanced ER+ Breast Cancer

22 février 2013 mis à jour par: Bristol-Myers Squibb

A Randomized, Double-Blind, Multi-Center Phase II Trial of Exemestane (Aromasin®) Plus Dasatinib Versus Exemestane Plus Placebo in Advanced Estrogen Receptor-Positive Breast Cancer After Disease Progression on a Non-Steroidal Aromatase Inhibitor (NSAI)

The purpose of this study is to determine whether exemestane plus dasatinib will be well-tolerated and will increase progression-free survival (PFS) in the treatment of advanced estrogen-receptor positive (ER+) breast cancer after disease progression (PD) on a non-steroidal aromatase inhibitor (NSAI).

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Type d'étude

Interventionnel

Inscription (Réel)

155

Phase

  • Phase 2

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • Espagne
      • Madrid, Espagne, 28041
        • Local Institution
      • Madrid, Espagne, 28033
        • Local Institution
      • Torrevieja, Espagne, 03186
        • Local Institution
  • France
      • Lille, France, 59000
        • Local Institution
      • Paris Cedex 13, France, 75651
        • Local Institution
      • Saint-Cloud Cedex, France, 92211
        • Local Institution
  • Irlande
      • Dublin, Irlande, 24
        • Local Institution
  • Pologne
      • Gdansk, Pologne, 80-952
        • Local Institution
      • Gdansk, Pologne, 80-462
        • Local Institution
      • Lodz, Pologne, 93-509
        • Local Institution
      • Opole, Pologne, 45-060
        • Local Institution
  • Royaume-Uni
    • Essex
      • Chelmsford, Essex, Royaume-Uni, CM1 7ET
        • Local Institution
    • Greater London
      • London, Greater London, Royaume-Uni, NW1 2BU
        • Local Institution
    • Warwickshire
      • Coventry, Warwickshire, Royaume-Uni, CV22DX
        • Local Institution
  • République tchèque
      • Hradec Kralove, République tchèque, 500 05
        • Local Institution
      • Prague 5, République tchèque, 150 06
        • Local Institution
  • Suède
      • Vasteras, Suède, 72189
        • Local Institution
  • États-Unis
    • California
      • Fountain Valley, California, États-Unis, 92708
        • Compassionate Cancer Care Medical Group, Inc
      • Riverside, California, États-Unis, 92501
        • Compassionate Cancer Care Medical Group Inc
    • Pennsylvania
      • Philadelphia, Pennsylvania, États-Unis, 19106
        • Pennsylvania Oncology/Hematology Associates
    • Tennessee
      • Memphis, Tennessee, États-Unis, 38120
        • The West Clinic

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans et plus (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  • Histologically-documented invasive estrogen receptor positive breast cancer , with tumor tissue from prior surgery available for analysis
  • Prior therapy with a non-steroidal aromatase inhibitor
  • Recurrent or progressive advanced breast cancer (locally-advanced or metastatic)
  • Documented breast cancer with tumor ≤ 28 days prior to study entry
  • Women who are NOT of childbearing potential
  • Must be able to take oral medication
  • Performance Status 0 or 1

Exclusion Criteria:

  • Pleural or pericardial effusion or ascites (of any etiology; Grade ≥ 1) within 6 months prior to study entry
  • Any chemotherapy, immunotherapy < 6 months before study entry. Any targeted therapy (eg. lapatinib) < 6 months before study entry, unless given in combination with an NSAI
  • Any antitumor therapy, including radiotherapy or hormonal therapy, within 15 days prior to study entry
  • Prior exposure to exemestane, any Src-family kinase inhibitor including dasatinib, to agents intended to control osteolytic disease other than bisphosphonates, or to any investigational agent for breast cancer
  • Concurrent or previous malignant disease requiring chemotherapy or radiation treatment within the prior 3 years
  • Significant bleeding disorder, or ongoing or recent clinically-significant gastrointestinal bleeding
  • Any serious cardiac condition, including congestive heart failure or myocardial infarction within 6 months, uncontrolled angina, or Class III or IV heart disease as defined by the New York Heart Association, baseline ejection fraction ≤ 40%, diagnosed congenital long QT syndrome, clinically-significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes), QTc interval > 450 msec at baseline (Fridericia correction)
  • Hematologic abnormality Grade ≥ 2
  • Hypocalcemia of Grade ≥ 1
  • Any Chemistry abnormality of Grade ≥ 2 [except Grade 2 indirect bilirubin permitted if diagnosed Gilbert's disease]
  • Pregnant Women and Women of Childbearing Potential (WOCBP)
  • Extremely lactose intolerant, in the judgment of treating physician (100 mg dasatinib contains 135 mg lactose, posing a problem only if intolerance is severe)
  • Receiving any of the following concomitant medications: Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Subjects must discontinue drug use at least 7 days prior to starting dasatinib)
  • Potent inhibitors of CYP3A4 isoenzyme
  • Prisoners or subjects who are involuntarily incarcerated; or subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Double

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Comparateur actif: UN
Médicament: Exemestane + Dasatinib
Tablets, Oral, Exemestane 25 mg + Dasatinib 100 mg, once daily, until disease progression or unacceptable toxicity
Autres noms:
  • BMS-354825
  • Sprycel®
Comparateur placebo: B
Médicament: Exemestane + Placebo
Tablets, Oral, Exemestane 25 mg + Placebo 100 mg, once daily, until disease progression or unacceptable toxicity

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Progression Free Survival (PFS) Distribution for Exemestane Plus Dasatinib vs Exemestane Plus Placebo
Délai: Prior to study therapy, at 8 week intervals until progression occurs (maximum participant PFS of 71 weeks)
PFS= The time (weeks) from date of randomization to date of progressive disease(PD). PFS for each randomization arm was estimated using the Kaplan-Meier product-limit method. A point estimate and a 95% confidence interval (CI) for the median PFS was computed for each randomization arm using the Brookmeyer & Crowley method. PD=Increase (≥ 20%) in sum of longest diameters from smallest value during study (including baseline).
Prior to study therapy, at 8 week intervals until progression occurs (maximum participant PFS of 71 weeks)
Participants With Disease Progression or Death for Exemestane Plus Dasatinib vs Exemestane Plus Placebo
Délai: Prior to study therapy, at 8 week intervals until progression occurs. Maximum participant PFS of ____ months)
PD is an increase (≥ 20%) in sum of longest diameters from smallest value during study (including baseline).
Prior to study therapy, at 8 week intervals until progression occurs. Maximum participant PFS of ____ months)

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Number of Participants With Best Overall Response
Délai: at 6 months
Complete response (CR) = Disappearance of all measurable and non-measurable lesions, and no new lesions; Partial response (PR) = Decrease ≥30% from baseline in sum of longest diameters (LD) of all measurable lesions, with neither appearance of new lesions nor unequivocal progression of non-measurable lesions. SD = Disease re-assessment not qualifying as CR, PR or PD(≥20% increase in sum of longest diameters from smallest value).
at 6 months
Percentage of Participants With Clinical Benefit (CB) for Exemestane Plus Dasatinib Arm vs Exemestane Plus Placebo Arm at 6 Months
Délai: at 6 months
CB = participants whose best response is CR, PR, or stable disease(SD). CR = Disappearance of all measurable and non-measurable lesions, and no new lesions; PR = Decrease ≥30% from baseline in sum of longest diameters of all measurable lesions, with neither appearance of new lesions nor unequivocal progression of non-measurable lesions. SD = Disease re-assessment not qualifying as CR, PR or PD(≥20% increase in sum of longest diameters from smallest value). Confidence interval computed by Clopper-Pearson method.
at 6 months
Percentage of Participants With Response in Exemestane Plus Dasatinib Arm and Exemestane Plus Placebo Arms
Délai: Prior to study therapy, at 8 week intervals until progression occurs (maximum participant response was 39 weeks)
Response= Proportion of response-evaluable participants whose best response is CR or PR. Confidence intervals was computed using the Clopper-Pearson method. CR = Disappearance of all measurable and non-measurable lesions, and no new lesions; PR = Decrease ≥30% from baseline in sum of longest diameters of all measurable lesions, with neither appearance of new lesions nor unequivocal progression of non-measurable lesions.
Prior to study therapy, at 8 week intervals until progression occurs (maximum participant response was 39 weeks)
Participants With Freedom-From-Progression (FFP) at 6 Months
Délai: at 6 months
FFP at month 6 is defined for the randomized participants who had the probability of neither progressing nor dying before 6 months.
at 6 months
Time to Response for Exemestane Plus Dasatinib Arm and Exemestane Plus Placebo Arms
Délai: Prior to study therapy, at 8 week intervals until CR or PR. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug, whichever is longer
Time to response is defined as time from first dose of study therapy until measurement criteria are first met for PR or CR (whichever is recorded first). CR = Disappearance of all measurable and non-measurable lesions, and no new lesions; PR = Decrease ≥30% from baseline in sum of longest diameters of all measurable lesions, with neither appearance of new lesions nor unequivocal progression of non-measurable lesions.
Prior to study therapy, at 8 week intervals until CR or PR. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug, whichever is longer
Duration of Response for Exemestane Plus Dasatinib Arm and Exemestane Plus Placebo Arms
Délai: Prior to study therapy, at 8 week intervals. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug, whichever is longer.
Duration of response is defined as the time from date that measurement criteria are first met for PR or CR until first date of documented PD or death. CR = Disappearance of all measurable and non-measurable lesions, and no new lesions; PR = Decrease ≥30% from baseline in sum of longest diameters of all measurable lesions, with neither appearance of new lesions nor unequivocal progression of non-measurable lesions. PD=Increase (≥ 20%) in sum of longest diameters from smallest value during study (including baseline).
Prior to study therapy, at 8 week intervals. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug, whichever is longer.
Changes in Participant-reported Pain Intensity in Participants With Bone Metastasis
Délai: Start of study, at treatment start, after 2, 4, and 8 weeks of therapy and every 8 weeks thereafter, at end-of-treatment. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug.
Pain intensity evaluated by administration of the Brief Pain Inventory - Short Form (BPI-sf). The BPI-sf is a psychometrically-validated instrument which measures both pain severity and functional interference caused by pain using an 11-point numerical rating scale. Severity of pain at its "worst", "least" and "on average" in the last 24 hours, and "right now" (ie, at the time the questionnaire is being filled out) is recorded using anchors of "no pain" = "0" and "pain as bad as you can imagine" = "10".
Start of study, at treatment start, after 2, 4, and 8 weeks of therapy and every 8 weeks thereafter, at end-of-treatment. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug.
Changes in Markers of Bone Lysis in Participants With Bone Metastasis
Délai: Screening, Day 1, after week 2, 4, and week 8 and subsequently every 8 weeks, at end-of-treatment. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug.
Assay for urinary N-telopeptide was used to evaluate Osteolytic activity.
Screening, Day 1, after week 2, 4, and week 8 and subsequently every 8 weeks, at end-of-treatment. Participants will remain on study (ie, last visit) until disease progression or 30 days after the last dose of study drug.
Number of Participants Who Died, Experienced Serious Adverse Events (SAEs), Adverse Events (AEs) or Discontinuations Due to AEs (as Per National Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events [CTCAE], Version 3.0)
Délai: From start of study drug therapy up to 30 days after the last dose. Median duration of therapy (on-study time) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded. Grade (GR)1 = mild, GR 2 = moderate, GR 3=severe, GR 4=life threatening, GR 5=death.
From start of study drug therapy up to 30 days after the last dose. Median duration of therapy (on-study time) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Number of Participants With Grade 1-4 Hematology Abnormalities (as Per the NCI CTCAE, Version 3.0)
Délai: Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment. Median duration (on-study) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Abnormalities were graded per NCI-CTC, Version 3.0 criteria. Grade (GR)1 = mild, GR 2 = moderate, GR 3 = severe, GR 4 = life threatening. Normal ranges are provided by the Local Laboratory and may vary according to sex and age. Granulocytes, GR 1;<LLN-1.5x 10^9/L, GR 2:<1.5-1.0x10^9/L, GR 3: <1.0 - 0.5x10^9/L, GR, 4: <0.5x10^9 /L; Hemoglobin, GR 1: <LLN-10.0 g/dL, GR 2: <10.0-8.0 g/dL, GR 3: <8.0-6.5 g/dL, GR, 4: <6.5g/dL; Platelets, GR 1: <LLN-75.0x10^9/L, GR 2: <75.0-50.0x10^9/L, GR 3: <50.0-25.0x10^9/L; Leukocytes, GR 1: <LLN-3.0x10^9/L, GR 2: <3.0-2.0x10^9/L, GR 4: <1.0x10^9/L.
Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment. Median duration (on-study) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Number of Participants With Grade 1-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Bilirubin, Calcium, Creatinine, and Albumin (as Per the NCI CTCAE, Version 3.0)
Délai: Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment. Median duration (on-study time) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Grade (GR) 1 = mild, GR 2 = moderate, GR 3 = severe, GR 4 = life threatening). Normal ranges are provided by the Local Laboratory and may vary according to sex and age. Alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, GR 1: >ULN-2.5 x ULN (upper limit of normal), GR 2: >2.5-5.0 x ULN, GR 3: 5.0-20.0 x ULN; Low calcium, GR 1: <LLN - 8.0 mg/dL, GR 2: <8.0-7.0 mg/dL, GR 4:<6.0 mg/dL; High calcium, GR 1:>ULN - 11.5 mg/dL; bilirubin, GR 1: >ULN-1.5 x ULN,GR 3: >3-10 x ULN; Creatinine, GR1:>ULN-1.5 x ULN, GR2: >1.5-3.0 x ULN; Albumin, GR1:<LLN-3 g/dL,GR2:<3-2 g/dL.
Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment. Median duration (on-study time) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Number of Participants With Grade 1-4 Serum Chemistry Abnormalities in Potassium, Magnesium, Sodium, Phosphorous, Uric Acid, and Bicarbonate (as Per the NCI CTCAE, Version 3.0)
Délai: Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment. Median duration (on-study time) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Grade (GR)1= mild, GR2= moderate, GR3= severe, GR4= life threatening. Ranges are provided by the local laboratory and may vary according to sex and age. Phosphorous, GR1:<LLN 2.5 mg/dL, GR2:<2.5-2.0 mg/dL, GR3: 1.0-<2.0 mg/dL; Low sodium,GR1:<LLN 130mmol/L, GR3:120-<130 mmol/L; High Magnesium, GR1 >ULN 3.0 mg/dL,GR 3:<0.3 0.8mg/dL; Uric acid, GR1:>ULN 10 mg/dL, GR4:>10 mg/dL; Low potassium, GR1:<LLN 3.0mmol/L,GR3:<3.0 2.5mmol/L; High potassium, GR1:>ULN-5.5 mmol/L, GR2:>5.5-6.0 mmol/L; Bicarbonate, GR1:<LLN-16 mmol/L; GR2:<16 - 11 mmol/L; Hig sodium, GR1:>ULN-150 mmol/L,GR2:>150-155 mmol/L.
Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment. Median duration (on-study time) was 14.29 and 15.29 weeks for dasatinib and placebo groups, respectively.
Number of Participants With Abnormalities in Vital Signs
Délai: Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment.
Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment.
Number of Participants With Abnormalities in Electrocardiograms
Délai: Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment.
Data was collected prior treatment with the study drug, after week 2, 4, and week 8, every 8 weeks thereafter and at the end of the treatment.

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Bristol-Myers Squibb

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Liens utiles

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 février 2009

Achèvement primaire (Réel)

1 mars 2011

Achèvement de l'étude (Réel)

1 décembre 2012

Dates d'inscription aux études

Première soumission

6 octobre 2008

Première soumission répondant aux critères de contrôle qualité

6 octobre 2008

Première publication (Estimation)

7 octobre 2008

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

28 février 2013

Dernière mise à jour soumise répondant aux critères de contrôle qualité

22 février 2013

Dernière vérification

1 juillet 2012

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • CA180-261

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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