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

Phase 2

Terminated

Conditions: Breast Neoplasms

Interventions: Drug: CC-486
Drug: Fulvestrant

Registration Number: NCT02374099

Lead Sponsor: Celgene

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).

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 97

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)].

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CC-486 and fulvestrant	CC-486	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.
CC-486 and fulvestrant	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.
Fulvestrant	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.

Trial Locations

Locations (35): Florida Cancer Specialists
🇺🇸
West Palm Beach, Florida, United States
Clinique Sainte Elisabeth - Service d'Oncologie
🇧🇪
Namur, Belgium
Universitatsklinikum Hamburg-Eppendorf / IVDP
🇩🇪
Hamburg, Germany
AZ Groeninge
🇧🇪
Kortrijk, Belgium
GasthuisZusters Antwerpen
🇧🇪
Wilrijk, Belgium
Clinical Research Alliance
🇺🇸
New York, New York, United States
Medical Oncology Associates
🇺🇸
Spokane, Washington, United States
Ospedale San Raffaele S.r.l.
🇮🇹
Milano, Italy
Policlinico S. Orsola - Malpighi
🇮🇹
Bologna, Italy
TU München - Klinikum rechts der Isar
🇩🇪
München, Germany
Hospital Ramon y Cajal
🇪🇸
Madrid, Spain
Hospital Universitario Vall D Hebron
🇪🇸
Barcelona, Spain
Istituto Nazionale Dei Tumori
🇮🇹
Milano, Italy
Arcispedale Santa Maria Nuova
🇮🇹
Reggio Emilia, Italy
Policlinico Universitario A Gemelli
🇮🇹
Roma, Italy
Hospital Virgen del Rocio
🇪🇸
Sevilla, Spain
Hospital Clinico Universitario Virgen de La Victoria
🇪🇸
Malaga, Spain
Hopital Pitie Salpetriere
🇫🇷
Paris, France
Institut Bergonie
🇫🇷
Borddeaux Cedex, France
Hamatologisch Onkologische Praxis Eppendorf
🇩🇪
Hamburg, Germany
Virginia G Piper Cancer Center
🇺🇸
Scottsdale, Arizona, United States
Ironwood Cancer and Research Center
🇺🇸
Chandler, Arizona, United States
Highlands Oncology Group
🇺🇸
Fayetteville, Arkansas, United States
University of Kansas Hospital
🇺🇸
Westwood, Kansas, United States
Henry Ford Health System
🇺🇸
Detroit, Michigan, United States
Grand Hopital de Charleroi
🇧🇪
Charleroi, Belgium
Centre Rene Gauducheau Centre de Lutte Contre Le Cancer Nantes Atlantique
🇫🇷
Saint Herblain, France
Centre Regional de lutte contre le cancer Paul Papin
🇫🇷
Angers, France
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
🇩🇪
Mainz, Germany
Complejo Universitario La Coruna
🇪🇸
La Coruna, Spain
IEO- Istituto Europeo di Oncologia
🇮🇹
Milano, Italy
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
🇮🇹
Torino, Piemonte, Italy
Hospital del Mar
🇪🇸
Barcelona, Spain
Policlinico Umberto I
🇮🇹
Roma, Italy
Hospital General Gregorio Maranon
🇪🇸
Madrid, Spain