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

Primary Purpose

Breast Neoplasms

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
CC-486
Fulvestrant
Sponsored by
Celgene
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Neoplasms focused on measuring Breast Cancer, Her2 -, ER+, CC-486 (ORAL AZACITIDINE), Metastatic Breast Cancer, Oral Azacitidine, Fulvestrant, Epigenetics

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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)].

Sites / Locations

  • Ironwood Cancer and Research Center
  • Virginia G Piper Cancer Center
  • Highlands Oncology Group
  • Florida Cancer Specialists
  • University of Kansas Hospital
  • Henry Ford Health System
  • Clinical Research Alliance
  • Medical Oncology Associates
  • Grand Hopital de Charleroi
  • AZ Groeninge
  • Clinique Sainte Elisabeth - Service d'Oncologie
  • GasthuisZusters Antwerpen
  • Centre Regional de lutte contre le cancer Paul Papin
  • Institut Bergonie
  • Hopital Pitie Salpetriere
  • Centre Rene Gauducheau Centre de Lutte Contre Le Cancer Nantes Atlantique
  • Universitatsklinikum Hamburg-Eppendorf / IVDP
  • Hamatologisch Onkologische Praxis Eppendorf
  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • TU München - Klinikum rechts der Isar
  • Policlinico S. Orsola - Malpighi
  • Ospedale San Raffaele S.r.l.
  • Istituto Nazionale Dei Tumori
  • IEO- Istituto Europeo di Oncologia
  • Arcispedale Santa Maria Nuova
  • Policlinico Umberto I
  • Policlinico Universitario A Gemelli
  • Azienda Ospedaliera Citta della Salute e della Scienza di Torino
  • Hospital del Mar
  • Hospital Universitario Vall D Hebron
  • Complejo Universitario La Coruna
  • Hospital General Gregorio Maranon
  • Hospital Ramon y Cajal
  • Hospital Clinico Universitario Virgen de La Victoria
  • Hospital Virgen del Rocio

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

CC-486 and fulvestrant

Fulvestrant

Arm Description

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 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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
January 22, 2015
Last Updated
December 12, 2018
Sponsor
Celgene
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1. Study Identification

Unique Protocol Identification Number
NCT02374099
Brief Title
Study to Assess the Efficacy and Safety of the Epigenetic Modifying Effects of CC-486 (Oral Azacitidine) in Combination With Fulvestrant
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Terminated
Study Start Date
March 13, 2015 (Actual)
Primary Completion Date
December 13, 2016 (Actual)
Study Completion Date
November 21, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Celgene

4. Oversight

Data Monitoring Committee
Yes

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Neoplasms
Keywords
Breast Cancer, Her2 -, ER+, CC-486 (ORAL AZACITIDINE), Metastatic Breast Cancer, Oral Azacitidine, Fulvestrant, Epigenetics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
97 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CC-486 and fulvestrant
Arm Type
Experimental
Arm Description
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.
Arm Title
Fulvestrant
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
CC-486
Other Intervention Name(s)
Oral Azacitidine
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Other Intervention Name(s)
Faslodex
Intervention Description
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.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
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
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
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

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)].
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ileana Elias, MD
Organizational Affiliation
Celgene
Official's Role
Study Director
Facility Information:
Facility Name
Ironwood Cancer and Research Center
City
Chandler
State/Province
Arizona
ZIP/Postal Code
85224
Country
United States
Facility Name
Virginia G Piper Cancer Center
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Facility Name
Highlands Oncology Group
City
Fayetteville
State/Province
Arkansas
ZIP/Postal Code
72703
Country
United States
Facility Name
Florida Cancer Specialists
City
West Palm Beach
State/Province
Florida
ZIP/Postal Code
33401
Country
United States
Facility Name
University of Kansas Hospital
City
Westwood
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Clinical Research Alliance
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Medical Oncology Associates
City
Spokane
State/Province
Washington
ZIP/Postal Code
99208
Country
United States
Facility Name
Grand Hopital de Charleroi
City
Charleroi
ZIP/Postal Code
6000
Country
Belgium
Facility Name
AZ Groeninge
City
Kortrijk
ZIP/Postal Code
8500
Country
Belgium
Facility Name
Clinique Sainte Elisabeth - Service d'Oncologie
City
Namur
ZIP/Postal Code
5000
Country
Belgium
Facility Name
GasthuisZusters Antwerpen
City
Wilrijk
ZIP/Postal Code
2610
Country
Belgium
Facility Name
Centre Regional de lutte contre le cancer Paul Papin
City
Angers
ZIP/Postal Code
49933
Country
France
Facility Name
Institut Bergonie
City
Borddeaux Cedex
ZIP/Postal Code
33076
Country
France
Facility Name
Hopital Pitie Salpetriere
City
Paris
ZIP/Postal Code
75651
Country
France
Facility Name
Centre Rene Gauducheau Centre de Lutte Contre Le Cancer Nantes Atlantique
City
Saint Herblain
ZIP/Postal Code
44805
Country
France
Facility Name
Universitatsklinikum Hamburg-Eppendorf / IVDP
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Hamatologisch Onkologische Praxis Eppendorf
City
Hamburg
ZIP/Postal Code
20249
Country
Germany
Facility Name
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
TU München - Klinikum rechts der Isar
City
München
ZIP/Postal Code
81675
Country
Germany
Facility Name
Policlinico S. Orsola - Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Ospedale San Raffaele S.r.l.
City
Milano
ZIP/Postal Code
20132
Country
Italy
Facility Name
Istituto Nazionale Dei Tumori
City
Milano
ZIP/Postal Code
20133
Country
Italy
Facility Name
IEO- Istituto Europeo di Oncologia
City
Milano
ZIP/Postal Code
20144
Country
Italy
Facility Name
Arcispedale Santa Maria Nuova
City
Reggio Emilia
ZIP/Postal Code
42100
Country
Italy
Facility Name
Policlinico Umberto I
City
Roma
ZIP/Postal Code
00161
Country
Italy
Facility Name
Policlinico Universitario A Gemelli
City
Roma
ZIP/Postal Code
00168
Country
Italy
Facility Name
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
City
Torino, Piemonte
ZIP/Postal Code
10126
Country
Italy
Facility Name
Hospital del Mar
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Facility Name
Hospital Universitario Vall D Hebron
City
Barcelona
ZIP/Postal Code
8035
Country
Spain
Facility Name
Complejo Universitario La Coruna
City
La Coruna
ZIP/Postal Code
15006
Country
Spain
Facility Name
Hospital General Gregorio Maranon
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Facility Name
Hospital Ramon y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital Clinico Universitario Virgen de La Victoria
City
Malaga
ZIP/Postal Code
29011
Country
Spain
Facility Name
Hospital Virgen del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain

12. IPD Sharing Statement

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

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