Trial Outcomes & Findings for Study to Assess the Efficacy and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine) in Combination With Fulvestrant (NCT NCT02374099)

Last Updated: 2018-12-14

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

97 participants

Primary outcome timeframe

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

Results posted on

2018-12-14

Participant Flow

The study was conducted at 35 sites in Spain, Germany, Belgium, Italy and the United States.

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.

Participant milestones

Participant milestones
Measure	CC-486 and Fulvestrant 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.	Fulvestrant 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.
Overall Study STARTED	48	49
Overall Study Participants Treated	46	48
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	48	49

Reasons for withdrawal

Reasons for withdrawal
Measure	CC-486 and Fulvestrant 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.	Fulvestrant 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.
Overall Study Adverse Event	1	0
Overall Study Progressive Disease	35	40
Overall Study Withdrawal by Subject	5	1
Overall Study Miscellaneous	2	3
Overall Study Randomized, but not treated	2	1
Overall Study Study Terminated by Sponsor	3	4

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CC-486 and Fulvestrant n=48 Participants 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.	Fulvestrant n=49 Participants 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 n=97 Participants Total of all reporting groups
Age, Continuous	62.6 years STANDARD_DEVIATION 10.99 • n=93 Participants	62.9 years STANDARD_DEVIATION 10.03 • n=4 Participants	62.7 years STANDARD_DEVIATION 10.46 • n=27 Participants
Age, Customized In utero	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Customized Preterm newborn infants (gestational age < 37 wks)	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Customized Newborns (0-27 days)	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Customized Infants and toddlers (28 days-23 months)	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Customized Children (2-11 years)	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Customized Adolescents (12-17 years)	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Customized Adults (18-64 years)	29 Participants n=93 Participants	25 Participants n=4 Participants	54 Participants n=27 Participants
Age, Customized From 65-84 years	19 Participants n=93 Participants	24 Participants n=4 Participants	43 Participants n=27 Participants
Age, Customized 85 years and over	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Sex: Female, Male Female	48 Participants n=93 Participants	49 Participants n=4 Participants	97 Participants n=27 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race White	34 Participants n=93 Participants	39 Participants n=4 Participants	73 Participants n=27 Participants
Race Asian	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race American Indian/Alaska Native	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race Not Collected or Reported	13 Participants n=93 Participants	9 Participants n=4 Participants	22 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 = Fully Active	36 Participants n=93 Participants	21 Participants n=4 Participants	57 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 1 = Restrictive but ambulatory	12 Participants n=93 Participants	28 Participants n=4 Participants	40 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 2 = = Ambulatory but unable to work	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 3 = Limited Self Care	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Histology of Primary Diagnosis Ductal (Scirrhous Carcinoma)	37 Participants n=93 Participants	38 Participants n=4 Participants	75 Participants n=27 Participants
Histology of Primary Diagnosis Lobular Carcinoma	7 Participants n=93 Participants	12 Participants n=4 Participants	19 Participants n=27 Participants
Histology of Primary Diagnosis Other, Not specified	4 Participants n=93 Participants	2 Participants n=4 Participants	6 Participants n=27 Participants
Histology of Primary Diagnosis Missing	2 Participants n=93 Participants	1 Participants n=4 Participants	3 Participants n=27 Participants
Time from Primary Diagnosis of Breast Cancer to Study Randomization	119.05 months STANDARD_DEVIATION 70.322 • n=93 Participants	95.57 months STANDARD_DEVIATION 76.434 • n=4 Participants	107.19 months STANDARD_DEVIATION 74.037 • n=27 Participants
Duration of Prior Hormonal Anti-Cancer Therapy	31.39 Months STANDARD_DEVIATION 14.830 • n=93 Participants	35.84 Months STANDARD_DEVIATION 27.409 • n=4 Participants	33.64 Months STANDARD_DEVIATION 22.097 • n=27 Participants

PRIMARY outcome

Timeframe: 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

Population: The Intent-to-treat population included all randomized participants regardless of whether the participant received any investigational product or had any efficacy assessments collected.

Outcome measures

Outcome measures
Measure	CC-486 and Fulvestrant n=48 Participants 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.	Fulvestrant n=49 Participants 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.
Kaplan-Meier Estimate of Progression Free Survival (PFS)	5.49 months Interval 2.07 to 8.25	5.46 months Interval 3.58 to 7.36

SECONDARY outcome

Timeframe: 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

Population: The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.

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.

Outcome measures

Outcome measures
Measure	CC-486 and Fulvestrant n=48 Participants 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.	Fulvestrant n=49 Participants 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.
Percentage of Participants Who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment	8.3 Percentage of Participants 95% Confidence Interval 2.32 • Interval 2.32 to 19.98	2.0 Percentage of Participants 95% Confidence Interval 0.05 • Interval 0.05 to 10.85

SECONDARY outcome

Timeframe: 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

Population: The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.

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.

Outcome measures

Outcome measures
Measure	CC-486 and Fulvestrant n=48 Participants 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.	Fulvestrant n=49 Participants 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.
Percentage of Participants Who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment	31.3 Percentage of Participants 95% Confidence Interval 18.66 • Interval 18.66 to 46.25	30.6 Percentage of Participants 95% Confidence Interval 18.25 • Interval 18.25 to 45.42

SECONDARY outcome

Timeframe: 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

Population: The ITT population included all randomized participants regardless of whether the participant received any IP or had any efficacy assessments collected.

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.

Outcome measures

Outcome measures
Measure	CC-486 and Fulvestrant n=48 Participants 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.	Fulvestrant n=49 Participants 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.
Kaplan Meier Estimate of Overall Survival	NA months Interval 13.7 to NA = indicates overall survival was not estimable due to the insufficient number of participants with events at the time of the cut-off date. The median OS was not reached.	NA months Interval 10.7 to NA = indicates overall survival was not estimable due to the insufficient number of participants with events at the time of the cut-off date. The median OS was not reached.

SECONDARY outcome

Timeframe: 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

Population: Only participants who had a confirmed CR or PR response are included.

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.

Outcome measures

Outcome measures
Measure	CC-486 and Fulvestrant n=48 Participants 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.	Fulvestrant n=49 Participants 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.
Kaplan Meier Estimate of Duration of Response (DoR)	NA months Interval 6.61 to NA = indicates duration of response was not estimable due to the data not being mature at the time of the data cut off date. The median DOR was not reached.	NA months NA = indicates duration of response was not estimable due to the data not being mature at the time of the data cut off date. The median DOR was not reached.

SECONDARY outcome

Timeframe: 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

Population: The safety population included all randomized participants who received at least 1 dose of IP.

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.

Outcome measures

Outcome measures
Measure	CC-486 and Fulvestrant n=46 Participants 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.	Fulvestrant n=48 Participants 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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE	46 Participants	45 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE Leading to Dose Interruption of any IP	22 Participants	3 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Treatment Related TEAE	46 Participants	31 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Treatment Related TEAE Grade 3 or 4 TEAE	29 Participants	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Treatment Related TEAE Grade 5 Death	0 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Grade 3 or 4 TEAE	32 Participants	15 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Grade 5 TEAE (Death)	2 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Serious TEAE	10 Participants	7 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE Leading to Stopping of Any IP	14 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) TEAE Leading to Dose Reduction of any IP	19 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Treatment Related Serious TEAE	4 Participants	0 Participants

Adverse Events

CC-486 and Fulvestrant

Serious events: 10 serious events

Other events: 45 other events

Deaths: 14 deaths

Fulvestrant

Serious events: 7 serious events

Other events: 44 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosure

Celgene Corporation

Phone: 888-260-1599

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	CC-486 and Fulvestrant n=46 participants at risk 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.	Fulvestrant n=48 participants at risk 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.
Blood and lymphatic system disorders Anaemia	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Cardiac disorders Pericardial effusion	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Gastrointestinal disorders Constipation	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Gastrointestinal disorders Gastrointestinal necrosis	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Gastrointestinal disorders Nausea	4.3% 2/46 • 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.	2.1% 1/48 • 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.
Gastrointestinal disorders Small intestinal obstruction	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Gastrointestinal disorders Vomiting	6.5% 3/46 • 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.	2.1% 1/48 • 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.
General disorders Chest pain	0.00% 0/46 • 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.	2.1% 1/48 • 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.
General disorders Fatigue	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Hepatobiliary disorders Hepatic failure	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Infections and infestations Pneumonia	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Musculoskeletal and connective tissue disorders Back pain	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Musculoskeletal and connective tissue disorders Neck pain	2.2% 1/46 • 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.	0.00% 0/48 • 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.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Nervous system disorders Cervical myelopathy	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.3% 2/46 • 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.	0.00% 0/48 • 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.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/46 • 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.	2.1% 1/48 • 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.
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.2% 1/46 • 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.	0.00% 0/48 • 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.

Measure	CC-486 and Fulvestrant n=46 participants at risk 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.	Fulvestrant n=48 participants at risk 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.
Gastrointestinal disorders Abdominal pain upper	13.0% 6/46 • 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.	2.1% 1/48 • 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.
Gastrointestinal disorders Constipation	41.3% 19/46 • 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.	20.8% 10/48 • 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.
Gastrointestinal disorders Diarrhoea	43.5% 20/46 • 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.	12.5% 6/48 • 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.
Gastrointestinal disorders Nausea	76.1% 35/46 • 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.	29.2% 14/48 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.5% 3/46 • 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.	14.6% 7/48 • 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.
Skin and subcutaneous tissue disorders Rash	8.7% 4/46 • 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.	0.00% 0/48 • 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.
Vascular disorders Hot flush	8.7% 4/46 • 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.	10.4% 5/48 • 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.
Gastrointestinal disorders Vomiting	71.7% 33/46 • 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.	10.4% 5/48 • 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.
General disorders Asthenia	34.8% 16/46 • 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.	20.8% 10/48 • 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.
General disorders Fatigue	28.3% 13/46 • 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.	25.0% 12/48 • 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.
General disorders Injection site pain	2.2% 1/46 • 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.	10.4% 5/48 • 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.
General disorders Oedema peripheral	2.2% 1/46 • 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.	6.2% 3/48 • 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.
General disorders Pyrexia	6.5% 3/46 • 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.	4.2% 2/48 • 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.
Infections and infestations Urinary tract infection	6.5% 3/46 • 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.	8.3% 4/48 • 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.
Infections and infestations Viral upper respiratory tract infection	6.5% 3/46 • 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.	6.2% 3/48 • 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.
Investigations Aspartate aminotransferase increased	2.2% 1/46 • 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.	10.4% 5/48 • 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.
Investigations Blood alkaline phosphatase increased	0.00% 0/46 • 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.	6.2% 3/48 • 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.
Investigations Weight decreased	6.5% 3/46 • 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.	2.1% 1/48 • 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.
Investigations White blood cell count decreased	6.5% 3/46 • 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.	0.00% 0/48 • 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.
Metabolism and nutrition disorders Decreased appetite	28.3% 13/46 • 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.	16.7% 8/48 • 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.
Metabolism and nutrition disorders Hyperuricaemia	2.2% 1/46 • 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.	6.2% 3/48 • 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.
Musculoskeletal and connective tissue disorders Arthralgia	13.0% 6/46 • 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.	18.8% 9/48 • 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.
Musculoskeletal and connective tissue disorders Back pain	6.5% 3/46 • 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.	14.6% 7/48 • 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.
Musculoskeletal and connective tissue disorders Bone pain	10.9% 5/46 • 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.	12.5% 6/48 • 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.
Musculoskeletal and connective tissue disorders Muscle spasms	8.7% 4/46 • 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.	2.1% 1/48 • 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.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	2.2% 1/46 • 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.	6.2% 3/48 • 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.3% 2/46 • 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.	14.6% 7/48 • 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.
Musculoskeletal and connective tissue disorders Myalgia	2.2% 1/46 • 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.	8.3% 4/48 • 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.
Musculoskeletal and connective tissue disorders Pain in extremity	6.5% 3/46 • 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.	12.5% 6/48 • 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.
Nervous system disorders Dizziness	6.5% 3/46 • 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.	8.3% 4/48 • 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.
Nervous system disorders Headache	10.9% 5/46 • 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.	10.4% 5/48 • 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.
Psychiatric disorders Anxiety	0.00% 0/46 • 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.	6.2% 3/48 • 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.
Psychiatric disorders Insomnia	4.3% 2/46 • 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.	8.3% 4/48 • 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.
Respiratory, thoracic and mediastinal disorders Cough	10.9% 5/46 • 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.	8.3% 4/48 • 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.
Blood and lymphatic system disorders Anaemia	2.2% 1/46 • 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.	6.2% 3/48 • 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.
Blood and lymphatic system disorders Neutropenia	21.7% 10/46 • 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.	0.00% 0/48 • 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.
Gastrointestinal disorders Abdominal pain	13.0% 6/46 • 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.	4.2% 2/48 • 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.