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

Breast Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02374099
• Other study ID #: CC-486-BRSTM-001
• Status: Terminated
• Phase: Phase 2
• Start date: March 13, 2015
• Est. completion date: November 21, 2017

Study information

• Verified date: December 2018
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Terminated
• Enrollment: 97
• Est. completion date: November 21, 2017
• Est. primary completion date: December 13, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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)].

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

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
• 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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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