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)
• Enrollment: 97
• Locations: 35
• Arms: 2
• Actual Duration (Months): 32.3
• Patients Per Site: 2.8
• Patients Per Site Per Month: 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
Breast Neoplasms	Drug: CC-486; Drug: Fulvestrant	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

• Keywords provided by Celgene: Breast Cancer; Her2 -; ER+; CC-486 (ORAL AZACITIDINE); Metastatic Breast Cancer; Oral Azacitidine; Fulvestrant; Epigenetics
• Additional relevant MeSH terms: Breast Neoplasms; Azacitidine; Fulvestrant; Cc-486

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.
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.