A clinical trial to see if the combination CC-486 plus fulvestrant is effectiveand safe, compared to fulvestrant alone, in patients with metastatic breastcancer that is estrogen receptor-positive and human epidermal growthfactor receptor 2-negative

Phase 1

• Conditions: Postmenopausal female subjects with estrogen receptor positive (ER+),human epidermal growth factor receptor 2 negative (HER2-) metastaticbreast cancer, who have progressed on an aromatase inhibitor (AI); MedDRA version: 19.0Level: PTClassification code 10006187Term: Breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 19.0Level: LLTClassification code 10070575Term: Estrogen receptor positive breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 19.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 19.0Level: LLTClassification code 10006204Term: Breast carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 19.0Level: LLTClassification code 10006315Term: Breast tumor malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 19.0Level: LLTClassification code 10006283Term: Breast neoplasm malignant femaleSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-003220-52-IT
• Lead Sponsor: CELGENE CORPORATIO

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-09-28
• Last Update Posted: 19 February 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Female
• Target Recruitment: 92

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study:

1. 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.

2. Subject is considered postmenopausal (ie, if one of the following criteria are met):

• Prior bilateral oophorectomy

•Age = 60 years and amenorrhea for 12 or more consecutive months in the absence of chemotherapy, hormonal therapy, or ovarian suppression

•Age < 60 years old and amenorrhea for 12 or more consecutive months (in the absence of chemotherapy, hormonal therapy, or ovarian suppression) and FSH and estradiol in the postmenopausal range

Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone
(LHRH) agonist is not permitted for induction of ovarian suppression in this trial.

3. Subject has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive breast cancer by local laboratory (based on most recently analyzed biopsy).

4. Subject has HER2-negative breast cancer (based on most recently analyzed biopsy)
defined as a negative in situ hybridization test or an 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.

5. Subject had disease refractory to an AI defined as either:

a.recurrence while on adjuvant treatment with an aromatase inhibitor or within 12 months of last treatment administration, or

b.progression while on an aromatase inhibitor or within one month of last treatment administration.

Note: The aromatase inhibitor does not have to be the last treatment prior to randomization. Other prior anticancer therapy, eg, tamoxifen, are also allowed. Subjects do not need to meet the definition of refractory to AI” within any specified time period prior to randomization. Subjects can receive any number of endocrine/hormonal lines of therapy before or after meeting the definition of refractory to AI”.

6. Subject has an ECOG performance status of 0-1.

Confidential and Proprietary 34 CC-486-BRSTM-001 Amendment 1.0 Final: 04 Dec 2014

7. Subject has radiological documented measurable disease (ie, at least one measureable lesion as per RECIST Version 1.1).

•If no measurable disease is present, then at least one predominantly lytic bone lesion must be present

8. Subject has adequate organ functions, evidenced by the following:

a. AST (SGOT), ALT (SGPT) = 2.5 x upper limit of normal range (ULN), or = 5 x
ULN range if liver metastasis present b. Total bilirubin = 1.5 x ULN
c. Creatinine = 1.5 x ULN

d. Potassium within normal range (according to local lab), or correctable with supplements

9. Subject has adequate bone marrow function, evidenced by the following:
a. ANC = 1.5 x 109 cells/L
b. Platelets = 100 x 109 cells/L

c. Hemoglobin = 9 g/dL

10. Subject understands and voluntarily signs an informed consent document prior to any study-related assessments/procedures are conducted.

11. Subject is able to adhere to the study visit schedule and other protocol requirements.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 55
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 37

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment:

1. Subject has received > 1 prior line of chemotherapy in the metastatic setting

2. Subject has received any chemotherapy within 21 days prior to randomization.

3. Subject has received prior treatment with fulvestrant.

4. Subject has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent.

5. Subject has symptomatic visceral crisis requiring chemotherapy per investigator judgment.

6. Subject has received another investigational therapy within 28 days or 5 half lives of randomization, whichever is longer.

7. Subject has not recovered from the acute toxic effects [Common Terminology Criteria for Adverse Events (CTCAE) grade = 1] of prior anticancer therapy, radiation, or major surgery/significant trauma (except alopecia or other toxicities not considered a safety risk for the subject at the investigators discretion).

8. Subject has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.
9. Subject has had radiotherapy = 4 weeks or limited field radiation for palliation = 2 weeks prior to starting study drug, and/or from whom = 30% of the bone marrow was irradiated.

10. Subject has a history of, or current symptomatic brain metastasis.

a. Patients with asymptomatic brain metastases may participate in this trial. The patient must have completed any prior local treatment for brain metastases = 28 days prior to the start of study treatment (including radiotherapy and/or surgery) and must be receiving no or low stable dose corticosteroids.

11. Subject has severe renal impairment (creatinine clearance < 30 ml/min).

12. Subject has any other malignancy within 5 years prior to randomization, with the exception of adequately treated in situ carcinoma of the cervix, uteri, or non- melanomatous skin cancer (all treatment of which should have been completed 6 months prior to enrollment).

13. Subject has an impaired ability to swallow oral medication.

14. Subject has a contraindication to receiving IM injections (eg, bleeding disorders, anticoagulant use).

15. Subject has a known or suspected hypersensitivity or other contraindication to fulvestrant, azacitidine, or any excipients used in the manufacture of fulvestrant and CC-
486 (Refer to Azacitidine Investigator Brochure).

16. Subject has a history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.

17. Subject has persistent diarrhea or malabsorption = NCI CTCAE Grade 2, despite medical management.

18. 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.

19. Subject has a known history or current diagnosis of Human Immunodeficiency Virus
(HIV) infection, regardless of treatment status.

20. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would, in the investigator’s judgment, contraindicate subject particip

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified