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
35
2
32.3
2.8
0.1

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 Disease Intervention/Treatment Phase
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

Arm Intervention/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

    Site City State Country Postal Code
    1 Ironwood Cancer and Research Center Chandler Arizona United States 85224
    2 Virginia G Piper Cancer Center Scottsdale Arizona United States 85258
    3 Highlands Oncology Group Fayetteville Arkansas United States 72703
    4 Florida Cancer Specialists West Palm Beach Florida United States 33401
    5 University of Kansas Hospital Westwood Kansas United States 66205
    6 Henry Ford Health System Detroit Michigan United States 48202
    7 Clinical Research Alliance New York New York United States 10021
    8 Medical Oncology Associates Spokane Washington United States 99208
    9 Grand Hopital de Charleroi Charleroi Belgium 6000
    10 AZ Groeninge Kortrijk Belgium 8500
    11 Clinique Sainte Elisabeth - Service d'Oncologie Namur Belgium 5000
    12 GasthuisZusters Antwerpen Wilrijk Belgium 2610
    13 Centre Regional de lutte contre le cancer Paul Papin Angers France 49933
    14 Institut Bergonie Borddeaux Cedex France 33076
    15 Hopital Pitie Salpetriere Paris France 75651
    16 Centre Rene Gauducheau Centre de Lutte Contre Le Cancer Nantes Atlantique Saint Herblain France 44805
    17 Universitatsklinikum Hamburg-Eppendorf / IVDP Hamburg Germany 20246
    18 Hamatologisch Onkologische Praxis Eppendorf Hamburg Germany 20249
    19 Universitätsmedizin der Johannes Gutenberg-Universität Mainz Mainz Germany 55131
    20 TU München - Klinikum rechts der Isar München Germany 81675
    21 Policlinico S. Orsola - Malpighi Bologna Italy 40138
    22 Ospedale San Raffaele S.r.l. Milano Italy 20132
    23 Istituto Nazionale Dei Tumori Milano Italy 20133
    24 IEO- Istituto Europeo di Oncologia Milano Italy 20144
    25 Arcispedale Santa Maria Nuova Reggio Emilia Italy 42100
    26 Policlinico Umberto I Roma Italy 00161
    27 Policlinico Universitario A Gemelli Roma Italy 00168
    28 Azienda Ospedaliera Citta della Salute e della Scienza di Torino Torino, Piemonte Italy 10126
    29 Hospital del Mar Barcelona Spain 08003
    30 Hospital Universitario Vall D Hebron Barcelona Spain 8035
    31 Complejo Universitario La Coruna La Coruna Spain 15006
    32 Hospital General Gregorio Maranon Madrid Spain 28007
    33 Hospital Ramon y Cajal Madrid Spain 28034
    34 Hospital Clinico Universitario Virgen de La Victoria Malaga Spain 29011
    35 Hospital Virgen del Rocio Sevilla Spain 41013

    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 Details The study was conducted at 35 sites in Spain, Germany, Belgium, Italy and the United States.
    Pre-assignment Detail The 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 Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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
    STARTED 48 49
    Participants Treated 46 48
    COMPLETED 0 0
    NOT COMPLETED 48 49

    Baseline Characteristics

    Arm/Group Title CC-486 and Fulvestrant Fulvestrant Total
    Arm/Group Description Participants 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 Participants 48 49 97
    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
    Title Kaplan-Meier Estimate of Progression Free Survival (PFS)
    Description 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.
    Time Frame 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

    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 Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Participants 48 49
    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 Hypothesis p-Value = 0.599
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.87
    Confidence Interval (2-Sided) 95%
    0.54 to 1.42
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis Hazard ratio and associated two-sided 95% confidence intervals (CI) were estimated by the Cox proportional hazard models.
    2. Secondary Outcome
    Title Percentage of Participants Who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment
    Description 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.
    Time Frame 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

    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 Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Participants 48 49
    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 Hypothesis p-Value = 0.1479
    Comments
    Method Fisher Exact
    Comments
    Method of Estimation Estimation Parameter Difference in Response Rates
    Estimated Value 6.3
    Confidence Interval (2-Sided) 95%
    -2.47 to 15.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The two-sided 95% confidence interval for the difference in ORR was estimated by the Wilson method.
    3. Secondary Outcome
    Title Percentage of Participants Who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment
    Description 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.
    Time Frame 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

    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 Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Participants 48 49
    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 Hypothesis p-Value = 0.1732
    Comments
    Method Fisher Exact
    Comments
    Method of Estimation Estimation Parameter Difference in Clinical Benefit Rate
    Estimated Value 0.7
    Confidence Interval (2-Sided) 95%
    -17.76 to 19.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The two-sided 95% confidence interval for the difference in clinical benefit rate was estimated by the Wilson method.
    4. Secondary Outcome
    Title Kaplan Meier Estimate of Overall Survival
    Description 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.
    Time Frame 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

    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 Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Participants 48 49
    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 Hypothesis p-Value = 0.2725
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.59
    Confidence Interval (2-Sided) 95%
    0.23 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis Hazard Ratio and associated two-sided 95% CI were estimated by the Cox proportional hazard model.
    5. Secondary Outcome
    Title Kaplan Meier Estimate of Duration of Response (DoR)
    Description 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.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    Only participants who had a confirmed CR or PR response are included.
    Arm/Group Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Participants 48 49
    Median (95% Confidence Interval) [months]
    NA
    NA
    6. Secondary Outcome
    Title Number of Participants With Treatment Emergent Adverse Events (TEAEs)
    Description 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.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    The safety population included all randomized participants who received at least 1 dose of IP.
    Arm/Group Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Participants 46 48
    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 Frame From 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 Title CC-486 and Fulvestrant Fulvestrant
    Arm/Group Description Participants 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 Fulvestrant Fulvestrant
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 14/46 (30.4%) 16/48 (33.3%)
    Serious Adverse Events
    CC-486 and Fulvestrant Fulvestrant
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/46 (21.7%) 7/48 (14.6%)
    Blood and lymphatic system disorders
    Anaemia 1/46 (2.2%) 0/48 (0%)
    Cardiac disorders
    Pericardial effusion 1/46 (2.2%) 0/48 (0%)
    Gastrointestinal disorders
    Constipation 1/46 (2.2%) 0/48 (0%)
    Gastrointestinal necrosis 1/46 (2.2%) 0/48 (0%)
    Nausea 2/46 (4.3%) 1/48 (2.1%)
    Small intestinal obstruction 1/46 (2.2%) 0/48 (0%)
    Vomiting 3/46 (6.5%) 1/48 (2.1%)
    General disorders
    Chest pain 0/46 (0%) 1/48 (2.1%)
    Fatigue 1/46 (2.2%) 0/48 (0%)
    Hepatobiliary disorders
    Hepatic failure 0/46 (0%) 1/48 (2.1%)
    Infections and infestations
    Pneumonia 1/46 (2.2%) 0/48 (0%)
    Injury, poisoning and procedural complications
    Hip fracture 0/46 (0%) 1/48 (2.1%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/46 (2.2%) 0/48 (0%)
    Muscular weakness 0/46 (0%) 1/48 (2.1%)
    Neck pain 1/46 (2.2%) 0/48 (0%)
    Pathological fracture 0/46 (0%) 1/48 (2.1%)
    Spinal osteoarthritis 0/46 (0%) 1/48 (2.1%)
    Nervous system disorders
    Cervical myelopathy 0/46 (0%) 1/48 (2.1%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 2/46 (4.3%) 0/48 (0%)
    Pulmonary embolism 0/46 (0%) 1/48 (2.1%)
    Respiratory failure 1/46 (2.2%) 0/48 (0%)
    Other (Not Including Serious) Adverse Events
    CC-486 and Fulvestrant Fulvestrant
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 45/46 (97.8%) 44/48 (91.7%)
    Blood and lymphatic system disorders
    Anaemia 1/46 (2.2%) 3/48 (6.3%)
    Neutropenia 10/46 (21.7%) 0/48 (0%)
    Gastrointestinal disorders
    Abdominal pain 6/46 (13%) 2/48 (4.2%)
    Abdominal pain upper 6/46 (13%) 1/48 (2.1%)
    Constipation 19/46 (41.3%) 10/48 (20.8%)
    Diarrhoea 20/46 (43.5%) 6/48 (12.5%)
    Nausea 35/46 (76.1%) 14/48 (29.2%)
    Vomiting 33/46 (71.7%) 5/48 (10.4%)
    General disorders
    Asthenia 16/46 (34.8%) 10/48 (20.8%)
    Fatigue 13/46 (28.3%) 12/48 (25%)
    Injection site pain 1/46 (2.2%) 5/48 (10.4%)
    Oedema peripheral 1/46 (2.2%) 3/48 (6.3%)
    Pyrexia 3/46 (6.5%) 2/48 (4.2%)
    Infections and infestations
    Urinary tract infection 3/46 (6.5%) 4/48 (8.3%)
    Viral upper respiratory tract infection 3/46 (6.5%) 3/48 (6.3%)
    Investigations
    Aspartate aminotransferase increased 1/46 (2.2%) 5/48 (10.4%)
    Blood alkaline phosphatase increased 0/46 (0%) 3/48 (6.3%)
    Weight decreased 3/46 (6.5%) 1/48 (2.1%)
    White blood cell count decreased 3/46 (6.5%) 0/48 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 13/46 (28.3%) 8/48 (16.7%)
    Hyperuricaemia 1/46 (2.2%) 3/48 (6.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 6/46 (13%) 9/48 (18.8%)
    Back pain 3/46 (6.5%) 7/48 (14.6%)
    Bone pain 5/46 (10.9%) 6/48 (12.5%)
    Muscle spasms 4/46 (8.7%) 1/48 (2.1%)
    Musculoskeletal chest pain 1/46 (2.2%) 3/48 (6.3%)
    Musculoskeletal pain 2/46 (4.3%) 7/48 (14.6%)
    Myalgia 1/46 (2.2%) 4/48 (8.3%)
    Pain in extremity 3/46 (6.5%) 6/48 (12.5%)
    Nervous system disorders
    Dizziness 3/46 (6.5%) 4/48 (8.3%)
    Headache 5/46 (10.9%) 5/48 (10.4%)
    Psychiatric disorders
    Anxiety 0/46 (0%) 3/48 (6.3%)
    Insomnia 2/46 (4.3%) 4/48 (8.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough 5/46 (10.9%) 4/48 (8.3%)
    Dyspnoea 3/46 (6.5%) 7/48 (14.6%)
    Skin and subcutaneous tissue disorders
    Rash 4/46 (8.7%) 0/48 (0%)
    Vascular disorders
    Hot flush 4/46 (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/Title Clinical Trial Disclosure
    Organization Celgene Corporation
    Phone 888-260-1599
    Email ClinicalTrialDisclosure@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