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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: CC-486
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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)].

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-486 and fulvestrant<br>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<br>* 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<br>* Other names: Oral Azacitidine;Drug: Fulvestrant<br>* 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.<br>* Other names: Faslodex;|
| Experimental: Fulvestrant<br>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<br>* 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.<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Progression Free Survival (PFS) | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Confirmed Complete Response (CR) or Partial Response (PR) to Treatment (Objective Response Rate) Based On the Investigator Assessment | 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. | 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 | 
| Percentage of Participants Who Achieved a Confirmed CR, PR or Stable Disease (SD) for ≥ 24 Weeks (Clinical Benefit Rate) by Investigator Assessment | 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. | 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 | 
| Kaplan Meier Estimate of Overall Survival | 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. | 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 | 
| Kaplan Meier Estimate of Duration of Response (DoR) | 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. | 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 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER+, Breast Cancer, Her2 -, CC-486 (ORAL AZACITIDINE), Metastatic Breast Cancer, Oral Azacitidine, Fulvestrant, Epigenetics