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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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ClinicalTrials.gov Identifier: NCT02374099
Recruitment Status : Terminated
First Posted : February 27, 2015
Results First Posted : December 14, 2018
Last Update Posted : December 14, 2018
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Breast Neoplasms Drug: CC-486 Drug: Fulvestrant Phase 2

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
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 : March 13, 2015
Actual Primary Completion Date : December 13, 2016
Actual Study Completion Date : November 21, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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 Name: 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 Name: 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 Name: Faslodex




Primary Outcome Measures :
  1. Kaplan-Meier Estimate of Progression Free Survival (PFS) [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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) [ 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 ]
    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) [ 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 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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)].

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02374099


Locations
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Sponsors and Collaborators
Celgene
Investigators
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Study Director: Ileana Elias, MD Celgene
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02374099    
Other Study ID Numbers: CC-486-BRSTM-001
First Posted: February 27, 2015    Key Record Dates
Results First Posted: December 14, 2018
Last Update Posted: December 14, 2018
Last Verified: December 2018
Keywords provided by Celgene:
Breast Cancer
Her2 -
ER+
CC-486 (ORAL AZACITIDINE)
Metastatic Breast Cancer
Oral Azacitidine
Fulvestrant
Epigenetics
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Azacitidine
Fulvestrant
Cc-486
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs