Study to Assess the Efficacy and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine) in Combination With Fulvestrant

Sponsor
Celgene (Industry)
Overall Status
Terminated
CT.gov ID
NCT02374099
Collaborator
(none)
97
Enrollment
35
Locations
2
Arms
32.3
Actual Duration (Months)
2.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study to Assess the Efficacy and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine) in Combination With Fulvestrant in Postmenopausal Women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 (HER2-) Metastatic Breast Cancer Who Have Progressed on an Aromatase Inhibitor (AI).

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

This is a Phase 2, open-label, two-arm study assessing the efficacy and safety of the combination of fulvestrant with CC-486 in subjects with ER+, HER2- metastatic breast cancer who have progressed after prior AI.

Approximately 92 participants will be enrolled and assigned randomly in a 1:1 ratio to one of two treatment arms:

  • Arm A: CC-486 300 mg and fulvestrant 500 mg: 46 subjects

  • Arm B: Fulvestrant 500 mg: 46 subjects Each cycle will be 28 days. CC-486 will be administered orally at a dose of 300 mg daily on days 1-21 of each 28-day cycle. Fulvestrant will be administered by intramuscular (IM) injection at a dose of 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent cycles.

Safety will be evaluated by an independent data monitoring committee (DMC) after a total of approximately 32 subjects have completed at least 1 treatment cycle.

Study Design

Study Type:
Interventional
Actual Enrollment :
97 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Randomized, Open-label, Two-arm Study to Assess the Efficacy and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine) in Combination With Fulvestrant in Postmenopausal Women With ER+, HER2- Metastatic Breast Cancer Who Have Progressed on an Aromatase Inhibitor
Actual Study Start Date :
Mar 13, 2015
Actual Primary Completion Date :
Dec 13, 2016
Actual Study Completion Date :
Nov 21, 2017

Arms and Interventions

ArmIntervention/Treatment
Experimental: CC-486 and fulvestrant

CC-486 300 mg by mouth (PO) daily on days 1-21 of each 28 day cycle and fulvestrant 500mg by intramuscular (IM) injection on Days 1 and 15 of cycle 1 and day 1 of each subsequent cycle every 28 days.

Drug: CC-486
Each cycle will be 28 days. CC-486 will be administered orally at a dose of 300 mg daily on days 1-21 of each 28-day cycle
Other Names:
  • Oral Azacitidine
  • Drug: Fulvestrant
    Fulvestrant will be administered by intramuscular (IM) injection at a dose of 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent cycles.
    Other Names:
  • Faslodex
  • Experimental: Fulvestrant

    Fulvestrant will be administered by intramuscular injection at a dose of 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent cycles.

    Drug: Fulvestrant
    Fulvestrant will be administered by intramuscular (IM) injection at a dose of 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent cycles.
    Other Names:
  • Faslodex
  • Outcome Measures

    Primary Outcome Measures

    1. Kaplan-Meier Estimate of Progression Free Survival (PFS) [From the date of randomization of study drug to the date of the cut off date of 13 December 2016; follow-up for PFS was 21 months]

      Progression-free survival was defined as the duration from the date of randomization to the date of disease progression (DP) based on investigator's assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or death (from any cause), whichever occurred first. Per RECIST 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions from nadir or appearance of a new lesion.

    Secondary Outcome Measures

    1. Percentage of Participants Who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment [Disease response was assessed every 8 weeks, for the first 24 weeks, then every 12 weeks until DP; from date of randomization of study drug to data cut-off date of 13 December 2016; follow-up for overall response was 21 months]

      Overall response rate was defined as the percentage of participants who achieved a confirmed complete response or partial response based on RECIST Version 1.1 criteria. RECIST criteria v 1.1 defined a CR as the disappearance of all target lesions and a PR with at least a 30% decrease in the sum of diameters of target lesions from baseline. The two-sided 95% exact binomial CI for each arm was estimated by the Clopper-Pearson method.

    2. Percentage of Participants Who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment [Disease response was assessed every 8 weeks, for the first 24 weeks, then every 12 weeks until DP; from date of randomization of study drug to the data cut-off date of 13 December 2016; follow-up for clinical benefit response was 21 months]

      Percentage of participants with CR or PR or SD was defined per RECIST criteria v 1.1 as a CR that includes a disappearance of all target lesions, a PR was defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline and SD as neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. The two-sided 95% exact binomial CI each arm was estimated by the Clopper-Pearson method.

    3. Kaplan Meier Estimate of Overall Survival [From the date of randomization of study drug to the data cut off date of 13 December 2016; participants were followed for overall survival for 21 months]

      Overall survival was defined as the time from the date of randomization to the date of death (from any cause). All participants who were lost to follow up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.

    4. Kaplan Meier Estimate of Duration of Response (DoR) [From the date of randomization of study drug to the data cut-off of 13 December 2016; follow up for duration of response was 21 months]

      Duration of response was defined as the time from the first tumor assessment when the confirmed CR/PR criterion was first met to the date of disease progression, based on investigator's assessment following RECIST Version 1.1 criteria.

    5. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Randomization to 28 days after the last dose of IP; those AEs known at any time thereafter being related to IP; up to the last subject last visit of 21 November 2017; TEAE follow-up occurred up to 155 weeks and 2 days]

      Treatment-emergent adverse events (TEAEs) were defined as any AEs that begin or worsen with an onset date on or after the date of the first dose of IP through 28 days after the last dose. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on the participant's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity as follows: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Subject is female ≥ 18 years of age (at the time of signing the informed consent form) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy.

    • Subject is considered postmenopausal

    • Subject has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive breast cancer by local laboratory (based on most recently analyzed biopsy).

    • Subject has human epidermal growth factor receptor 2 negative (HER2-) breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization test or an Immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.

    • Subject had disease refractory to an AI

    • Subject has an Eastern Cooperative Oncology Group ( ECOG) performance status of 0-1.

    • Subject has radiological documented measurable disease (ie, at least one measureable lesion as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1).

    • If no measurable disease is present, then at least one predominantly lytic bone lesion must be present

    • Subject has adequate organ function.

    • Subject has adequate bone marrow function.

    Exclusion Criteria:
    • Subject has received > 1 prior line of chemotherapy in the metastatic setting

    • Subject has received any chemotherapy within 21 days prior to randomization.

    • Subject has received prior treatment with fulvestrant.

    • Subject has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent.

    • Subject has a history of, or current symptomatic brain metastasis.

    • Subject has severe renal impairment (creatinine clearance < 30 ml/min).

    • Subject has an impaired ability to swallow oral medication.

    • Subject has a contraindication to receiving IM injections (eg, bleeding disorders, anticoagulant use).

    • Subject has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.

    • Subject is a female of Childbearing Potential [defined as a sexually mature woman who (1) has not undergone hysterectomy (the surgical removal of the uterus) or bilateral oopherectomy (the surgical removal of both ovaries) or (2) has not been naturally postmenopausal for at least 12 consecutive months (ie, has had menses at any time during the preceding 12 consecutive months)].

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Ironwood Cancer and Research CenterChandlerArizonaUnited States85224
    2Virginia G Piper Cancer CenterScottsdaleArizonaUnited States85258
    3Highlands Oncology GroupFayettevilleArkansasUnited States72703
    4Florida Cancer SpecialistsWest Palm BeachFloridaUnited States33401
    5University of Kansas HospitalWestwoodKansasUnited States66205
    6Henry Ford Health SystemDetroitMichiganUnited States48202
    7Clinical Research AllianceNew YorkNew YorkUnited States10021
    8Medical Oncology AssociatesSpokaneWashingtonUnited States99208
    9Grand Hopital de CharleroiCharleroiBelgium6000
    10AZ GroeningeKortrijkBelgium8500
    11Clinique Sainte Elisabeth - Service d'OncologieNamurBelgium5000
    12GasthuisZusters AntwerpenWilrijkBelgium2610
    13Centre Regional de lutte contre le cancer Paul PapinAngersFrance49933
    14Institut BergonieBorddeaux CedexFrance33076
    15Hopital Pitie SalpetriereParisFrance75651
    16Centre Rene Gauducheau Centre de Lutte Contre Le Cancer Nantes AtlantiqueSaint HerblainFrance44805
    17Universitatsklinikum Hamburg-Eppendorf / IVDPHamburgGermany20246
    18Hamatologisch Onkologische Praxis EppendorfHamburgGermany20249
    19Universitätsmedizin der Johannes Gutenberg-Universität MainzMainzGermany55131
    20TU München - Klinikum rechts der IsarMünchenGermany81675
    21Policlinico S. Orsola - MalpighiBolognaItaly40138
    22Ospedale San Raffaele S.r.l.MilanoItaly20132
    23Istituto Nazionale Dei TumoriMilanoItaly20133
    24IEO- Istituto Europeo di OncologiaMilanoItaly20144
    25Arcispedale Santa Maria NuovaReggio EmiliaItaly42100
    26Policlinico Umberto IRomaItaly00161
    27Policlinico Universitario A GemelliRomaItaly00168
    28Azienda Ospedaliera Citta della Salute e della Scienza di TorinoTorino, PiemonteItaly10126
    29Hospital del MarBarcelonaSpain08003
    30Hospital Universitario Vall D HebronBarcelonaSpain8035
    31Complejo Universitario La CorunaLa CorunaSpain15006
    32Hospital General Gregorio MaranonMadridSpain28007
    33Hospital Ramon y CajalMadridSpain28034
    34Hospital Clinico Universitario Virgen de La VictoriaMalagaSpain29011
    35Hospital Virgen del RocioSevillaSpain41013

    Sponsors and Collaborators

    • Celgene

    Investigators

    • Study Director: Ileana Elias, MD, Celgene

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT02374099
    Other Study ID Numbers:
    • CC-486-BRSTM-001
    First Posted:
    Feb 27, 2015
    Last Update Posted:
    Dec 14, 2018
    Last Verified:
    Dec 1, 2018

    Study Results

    Participant Flow

    Recruitment DetailsThe study was conducted at 35 sites in Spain, Germany, Belgium, Italy and the United States.
    Pre-assignment DetailThe study enrolled adult, postmenopausal women, with metastatic breast cancer who progressed on an aromatase inhibitor. Participants were randomly assigned in a 1:1 ratio to one of two treatment arms to CC-486 tablets and fulvestrant or fulvestrant alone.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Period Title: Overall Study
    STARTED4849
    Participants Treated4648
    COMPLETED00
    NOT COMPLETED4849

    Baseline Characteristics

    Arm/Group TitleCC-486 and FulvestrantFulvestrantTotal
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.Total of all reporting groups
    Overall Participants484997
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    62.6
    (10.99)
    62.9
    (10.03)
    62.7
    (10.46)
    Age, Customized (Count of Participants)
    In utero
    0
    0%
    0
    0%
    0
    0%
    Preterm newborn infants (gestational age < 37 wks)
    0
    0%
    0
    0%
    0
    0%
    Newborns (0-27 days)
    0
    0%
    0
    0%
    0
    0%
    Infants and toddlers (28 days-23 months)
    0
    0%
    0
    0%
    0
    0%
    Children (2-11 years)
    0
    0%
    0
    0%
    0
    0%
    Adolescents (12-17 years)
    0
    0%
    0
    0%
    0
    0%
    Adults (18-64 years)
    29
    60.4%
    25
    51%
    54
    55.7%
    From 65-84 years
    19
    39.6%
    24
    49%
    43
    44.3%
    85 years and over
    0
    0%
    0
    0%
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    48
    100%
    49
    100%
    97
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Race (Count of Participants)
    White
    34
    70.8%
    39
    79.6%
    73
    75.3%
    Asian
    0
    0%
    1
    2%
    1
    1%
    American Indian/Alaska Native
    1
    2.1%
    0
    0%
    1
    1%
    Not Collected or Reported
    13
    27.1%
    9
    18.4%
    22
    22.7%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Count of Participants)
    0 = Fully Active
    36
    75%
    21
    42.9%
    57
    58.8%
    1 = Restrictive but ambulatory
    12
    25%
    28
    57.1%
    40
    41.2%
    2 = = Ambulatory but unable to work
    0
    0%
    0
    0%
    0
    0%
    3 = Limited Self Care
    0
    0%
    0
    0%
    0
    0%
    Histology of Primary Diagnosis (Number) [Number]
    Ductal (Scirrhous Carcinoma)
    37
    77.1%
    38
    77.6%
    75
    77.3%
    Lobular Carcinoma
    7
    14.6%
    12
    24.5%
    19
    19.6%
    Other, Not specified
    4
    8.3%
    2
    4.1%
    6
    6.2%
    Missing
    2
    4.2%
    1
    2%
    3
    3.1%
    Time from Primary Diagnosis of Breast Cancer to Study Randomization (months) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [months]
    119.05
    (70.322)
    95.57
    (76.434)
    107.19
    (74.037)
    Duration of Prior Hormonal Anti-Cancer Therapy (Months) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Months]
    31.39
    (14.830)
    35.84
    (27.409)
    33.64
    (22.097)

    Outcome Measures

    1. Primary Outcome
    TitleKaplan-Meier Estimate of Progression Free Survival (PFS)
    DescriptionProgression-free survival was defined as the duration from the date of randomization to the date of disease progression (DP) based on investigator's assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 or death (from any cause), whichever occurred first. Per RECIST 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions from nadir or appearance of a new lesion.
    Time FrameFrom the date of randomization of study drug to the date of the cut off date of 13 December 2016; follow-up for PFS was 21 months

    Outcome Measure Data

    Analysis Population Description
    The Intent-to-treat population included all randomized participants regardless of whether the participant received any investigational product or had any efficacy assessments collected.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Measure Participants4849
    Median (95% Confidence Interval) [months]
    5.49
    5.46
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CC-486 and Fulvestrant, Fulvestrant
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value= 0.599
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.87
    Confidence Interval (2-Sided) 95%
    0.54 to 1.42
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical AnalysisHazard ratio and associated two-sided 95% confidence intervals (CI) were estimated by the Cox proportional hazard models.
    2. Secondary Outcome
    TitlePercentage of Participants Who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment
    DescriptionOverall response rate was defined as the percentage of participants who achieved a confirmed complete response or partial response based on RECIST Version 1.1 criteria. RECIST criteria v 1.1 defined a CR as the disappearance of all target lesions and a PR with at least a 30% decrease in the sum of diameters of target lesions from baseline. The two-sided 95% exact binomial CI for each arm was estimated by the Clopper-Pearson method.
    Time FrameDisease response was assessed every 8 weeks, for the first 24 weeks, then every 12 weeks until DP; from date of randomization of study drug to data cut-off date of 13 December 2016; follow-up for overall response was 21 months

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Measure Participants4849
    Number (95% Confidence Interval) [Percentage of Participants]
    8.3
    (2.32) 17.3%
    2.0
    (0.05) 4.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CC-486 and Fulvestrant, Fulvestrant
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value= 0.1479
    Comments
    MethodFisher Exact
    Comments
    Method of EstimationEstimation ParameterDifference in Response Rates
    Estimated Value6.3
    Confidence Interval (2-Sided) 95%
    -2.47 to 15.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical AnalysisThe two-sided 95% confidence interval for the difference in ORR was estimated by the Wilson method.
    3. Secondary Outcome
    TitlePercentage of Participants Who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment
    DescriptionPercentage of participants with CR or PR or SD was defined per RECIST criteria v 1.1 as a CR that includes a disappearance of all target lesions, a PR was defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline and SD as neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. The two-sided 95% exact binomial CI each arm was estimated by the Clopper-Pearson method.
    Time FrameDisease response was assessed every 8 weeks, for the first 24 weeks, then every 12 weeks until DP; from date of randomization of study drug to the data cut-off date of 13 December 2016; follow-up for clinical benefit response was 21 months

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Measure Participants4849
    Number (95% Confidence Interval) [Percentage of Participants]
    31.3
    (18.66) 65.2%
    30.6
    (18.25) 62.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CC-486 and Fulvestrant, Fulvestrant
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value= 0.1732
    Comments
    MethodFisher Exact
    Comments
    Method of EstimationEstimation ParameterDifference in Clinical Benefit Rate
    Estimated Value0.7
    Confidence Interval (2-Sided) 95%
    -17.76 to 19.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical AnalysisThe two-sided 95% confidence interval for the difference in clinical benefit rate was estimated by the Wilson method.
    4. Secondary Outcome
    TitleKaplan Meier Estimate of Overall Survival
    DescriptionOverall survival was defined as the time from the date of randomization to the date of death (from any cause). All participants who were lost to follow up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.
    Time FrameFrom the date of randomization of study drug to the data cut off date of 13 December 2016; participants were followed for overall survival for 21 months

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Measure Participants4849
    Median (95% Confidence Interval) [months]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection CC-486 and Fulvestrant, Fulvestrant
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value= 0.2725
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.59
    Confidence Interval (2-Sided) 95%
    0.23 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical AnalysisHazard Ratio and associated two-sided 95% CI were estimated by the Cox proportional hazard model.
    5. Secondary Outcome
    TitleKaplan Meier Estimate of Duration of Response (DoR)
    DescriptionDuration of response was defined as the time from the first tumor assessment when the confirmed CR/PR criterion was first met to the date of disease progression, based on investigator's assessment following RECIST Version 1.1 criteria.
    Time FrameFrom the date of randomization of study drug to the data cut-off of 13 December 2016; follow up for duration of response was 21 months

    Outcome Measure Data

    Analysis Population Description
    Only participants who had a confirmed CR or PR response are included.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Measure Participants4849
    Median (95% Confidence Interval) [months]
    NA
    NA
    6. Secondary Outcome
    TitleNumber of Participants With Treatment Emergent Adverse Events (TEAEs)
    DescriptionTreatment-emergent adverse events (TEAEs) were defined as any AEs that begin or worsen with an onset date on or after the date of the first dose of IP through 28 days after the last dose. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on the participant's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity as follows: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death.
    Time FrameRandomization to 28 days after the last dose of IP; those AEs known at any time thereafter being related to IP; up to the last subject last visit of 21 November 2017; TEAE follow-up occurred up to 155 weeks and 2 days

    Outcome Measure Data

    Analysis Population Description
    The safety population included all randomized participants who received at least 1 dose of IP.
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    Measure Participants4648
    TEAE
    46
    95.8%
    45
    91.8%
    Grade 3 or 4 TEAE
    32
    66.7%
    15
    30.6%
    Grade 5 TEAE (Death)
    2
    4.2%
    1
    2%
    Serious TEAE
    10
    20.8%
    7
    14.3%
    TEAE Leading to Stopping of Any IP
    14
    29.2%
    1
    2%
    TEAE Leading to Dose Reduction of any IP
    19
    39.6%
    0
    0%
    TEAE Leading to Dose Interruption of any IP
    22
    45.8%
    3
    6.1%
    Treatment Related TEAE
    46
    95.8%
    31
    63.3%
    Treatment Related TEAE Grade 3 or 4 TEAE
    29
    60.4%
    2
    4.1%
    Treatment Related TEAE Grade 5 Death
    0
    0%
    0
    0%
    Treatment Related Serious TEAE
    4
    8.3%
    0
    0%

    Adverse Events

    Time FrameFrom randomization date to 28 days after the last dose of IP; those AEs known at any time thereafter being related to IP; up to last subject last visit date of 21 November 2017.
    Adverse Event Reporting Description
    Arm/Group TitleCC-486 and FulvestrantFulvestrant
    Arm/Group DescriptionParticipants received CC-486 tablets by mouth (PO) daily (QD) on days 1-21 of each 28 day treatment cycle and fulvestrant 500 mg by intramuscular injection (IM) on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up withdrawal of consent, or lost to follow-up.Participants received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of cycle 1 and on day 1 only in subsequent cycles until disease progression, start of new anticancer therapy, death, withdrawal of consent, or lost to follow-up.
    All Cause Mortality
    CC-486 and FulvestrantFulvestrant
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total14/46 (30.4%) 16/48 (33.3%)
    Serious Adverse Events
    CC-486 and FulvestrantFulvestrant
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total10/46 (21.7%) 7/48 (14.6%)
    Blood and lymphatic system disorders
    Anaemia1/46 (2.2%) 0/48 (0%)
    Cardiac disorders
    Pericardial effusion1/46 (2.2%) 0/48 (0%)
    Gastrointestinal disorders
    Constipation1/46 (2.2%) 0/48 (0%)
    Gastrointestinal necrosis1/46 (2.2%) 0/48 (0%)
    Nausea2/46 (4.3%) 1/48 (2.1%)
    Small intestinal obstruction1/46 (2.2%) 0/48 (0%)
    Vomiting3/46 (6.5%) 1/48 (2.1%)
    General disorders
    Chest pain0/46 (0%) 1/48 (2.1%)
    Fatigue1/46 (2.2%) 0/48 (0%)
    Hepatobiliary disorders
    Hepatic failure0/46 (0%) 1/48 (2.1%)
    Infections and infestations
    Pneumonia1/46 (2.2%) 0/48 (0%)
    Injury, poisoning and procedural complications
    Hip fracture0/46 (0%) 1/48 (2.1%)
    Musculoskeletal and connective tissue disorders
    Back pain1/46 (2.2%) 0/48 (0%)
    Muscular weakness0/46 (0%) 1/48 (2.1%)
    Neck pain1/46 (2.2%) 0/48 (0%)
    Pathological fracture0/46 (0%) 1/48 (2.1%)
    Spinal osteoarthritis0/46 (0%) 1/48 (2.1%)
    Nervous system disorders
    Cervical myelopathy0/46 (0%) 1/48 (2.1%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea2/46 (4.3%) 0/48 (0%)
    Pulmonary embolism0/46 (0%) 1/48 (2.1%)
    Respiratory failure1/46 (2.2%) 0/48 (0%)
    Other (Not Including Serious) Adverse Events
    CC-486 and FulvestrantFulvestrant
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total45/46 (97.8%) 44/48 (91.7%)
    Blood and lymphatic system disorders
    Anaemia1/46 (2.2%) 3/48 (6.3%)
    Neutropenia10/46 (21.7%) 0/48 (0%)
    Gastrointestinal disorders
    Abdominal pain6/46 (13%) 2/48 (4.2%)
    Abdominal pain upper6/46 (13%) 1/48 (2.1%)
    Constipation19/46 (41.3%) 10/48 (20.8%)
    Diarrhoea20/46 (43.5%) 6/48 (12.5%)
    Nausea35/46 (76.1%) 14/48 (29.2%)
    Vomiting33/46 (71.7%) 5/48 (10.4%)
    General disorders
    Asthenia16/46 (34.8%) 10/48 (20.8%)
    Fatigue13/46 (28.3%) 12/48 (25%)
    Injection site pain1/46 (2.2%) 5/48 (10.4%)
    Oedema peripheral1/46 (2.2%) 3/48 (6.3%)
    Pyrexia3/46 (6.5%) 2/48 (4.2%)
    Infections and infestations
    Urinary tract infection3/46 (6.5%) 4/48 (8.3%)
    Viral upper respiratory tract infection3/46 (6.5%) 3/48 (6.3%)
    Investigations
    Aspartate aminotransferase increased1/46 (2.2%) 5/48 (10.4%)
    Blood alkaline phosphatase increased0/46 (0%) 3/48 (6.3%)
    Weight decreased3/46 (6.5%) 1/48 (2.1%)
    White blood cell count decreased3/46 (6.5%) 0/48 (0%)
    Metabolism and nutrition disorders
    Decreased appetite13/46 (28.3%) 8/48 (16.7%)
    Hyperuricaemia1/46 (2.2%) 3/48 (6.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia6/46 (13%) 9/48 (18.8%)
    Back pain3/46 (6.5%) 7/48 (14.6%)
    Bone pain5/46 (10.9%) 6/48 (12.5%)
    Muscle spasms4/46 (8.7%) 1/48 (2.1%)
    Musculoskeletal chest pain1/46 (2.2%) 3/48 (6.3%)
    Musculoskeletal pain2/46 (4.3%) 7/48 (14.6%)
    Myalgia1/46 (2.2%) 4/48 (8.3%)
    Pain in extremity3/46 (6.5%) 6/48 (12.5%)
    Nervous system disorders
    Dizziness3/46 (6.5%) 4/48 (8.3%)
    Headache5/46 (10.9%) 5/48 (10.4%)
    Psychiatric disorders
    Anxiety0/46 (0%) 3/48 (6.3%)
    Insomnia2/46 (4.3%) 4/48 (8.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough5/46 (10.9%) 4/48 (8.3%)
    Dyspnoea3/46 (6.5%) 7/48 (14.6%)
    Skin and subcutaneous tissue disorders
    Rash4/46 (8.7%) 0/48 (0%)
    Vascular disorders
    Hot flush4/46 (8.7%) 5/48 (10.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Results from a center cannot be submitted for publication before results of multicenter study are published unless it is > 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission and defer publication to permit patent applications.

    Results Point of Contact

    Name/TitleClinical Trial Disclosure
    OrganizationCelgene Corporation
    Phone888-260-1599
    EmailClinicalTrialDisclosure@Celgene.com
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT02374099
    Other Study ID Numbers:
    • CC-486-BRSTM-001
    First Posted:
    Feb 27, 2015
    Last Update Posted:
    Dec 14, 2018
    Last Verified:
    Dec 1, 2018