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A Phase II Study Comparing The Efficacy Of Venetoclax + Fulvestrant Vs. Fulvestrant In Women With Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy

NCT03584009

Description:

This is a Phase II, multicenter, open-label, randomized study to compare the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone in women with ER+, HER2-negative, inoperable, locally advanced or MBC who experienced disease recurrence or progression during or after treatment with CDK4/6i therapy for at least 8 weeks.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II Study Comparing The Efficacy Of Venetoclax + Fulvestrant Vs. Fulvestrant In Women With Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy
  • Official Title: A Phase II, Multicenter, Randomized Study To Compare The Efficacy Of Venetoclax Plus Fulvestrant Versus Fulvestrant In Women With Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy

Clinical Trial IDs

  • ORG STUDY ID: WO40181
  • SECONDARY ID: 2017-005118-74
  • NCT ID: NCT03584009

Conditions

  • Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer

Interventions

DrugSynonymsArms
VenetoclaxVenetoclax + Fulvestrant
FulvestrantVenetoclax + Fulvestrant

Purpose

This is a Phase II, multicenter, open-label, randomized study to compare the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone in women with ER+, HER2-negative, inoperable, locally advanced or MBC who experienced disease recurrence or progression during or after treatment with CDK4/6i therapy for at least 8 weeks.

Trial Arms

NameTypeDescriptionInterventions
Venetoclax + FulvestrantExperimentalParticipants in the venetoclax arm will receive venetoclax, taken orally and fulvestrant administered as IM injections until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined end of the study (2 years after the last patient is enrolled) which ever occur first.
  • Venetoclax
  • Fulvestrant
FulvestrantActive ComparatorParticipants will receive fulvestrant administered as IM (intramuscular) injections. No crossover to the venetoclax arm is permitted. Study treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined end of the study (2 years after the last patient is enrolled) which ever occur first.
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria:

          -  Histological or cytological confirmation of estrogen receptor-positive (ER+) invasive
             carcinoma of the breast. ER+, HER2- negative invasive carcinoma of the breast with
             evaluable sample for BCL-2 IHC value at the time of screening.

          -  Evidence of metastatic or locally advanced disease not amenable to surgical or local
             therapy with curative intent

          -  Be postmenopausal

          -  Pre- or perimenopausal women amenable to being treated with the luteinizing
             hormone-releasing hormone (LHRH) agonist goserelin

          -  Participants must not have received more than two prior lines of hormonal therapy in
             the locally advanced or metastatic setting. In addition, at least one line of
             treatment must be a CDK4/6i AND participants must have experienced disease recurrence
             or progression during or after CDK4/6i therapy, which must have been administered for
             a minimum of 8 weeks prior to progression.

          -  Participants for whom endocrine therapy (e.g., fulvestrant) is recommended and
             treatment with cytotoxic chemotherapy is not indicated at the time of entry into the
             study, as per national or local treatment guidelines

          -  Women of childbearing potential (i.e., not postmenopausal for at least 12 months or
             surgically sterile) must have a negative serum pregnancy test result at screening,
             within 14 days prior to the first study drug administration

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use non-hormonal contraceptive methods with a failure
             rate of <1% per year during the treatment period and for 30 days after the last dose
             of study drug

          -  Willing to provide tumor biopsy sample

          -  Have at least one measurable lesion via RECIST v1.1

          -  Have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1

          -  Have adequate organ and marrow function

          -  Have a life expectancy > 3 months

          -  To full fill the coagulation requirements for patient with or without therapeutic
             anticoagulation

        Exclusion criteria:

          -  Prior treatment with fulvestrant or other selective estrogen receptor degraders
             (SERDs), venetoclax, or any agent whose mechanism of action is to inhibit BCL-2

          -  Pregnant, lactating, or intending to become pregnant during the study

          -  Known untreated or active Central Nervous System (CNS) metastases (progressing or
             requiring anticonvulsants or corticosteroids for symptomatic control

          -  Any anti-cancer therapy received within 21 days of the first dose of study drug,
             including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, antineoplastic
             vaccines, or other investigational therapy. (Radiotherapy with palliative intent to
             non-target sites is allowed).

          -  Concurrent radiotherapy to any site or prior radiotherapy within 21 days of Cycle 1
             Day 1 or previous radiotherapy to the target lesion sites (the sites that are to be
             followed for determination of a response) or prior radiotherapy to > 25% of bone
             marrow

          -  Current severe, uncontrolled, systemic disease (e.g., clinically significant
             cardiovascular, pulmonary, metabolic or infectious disease

          -  Any major surgery within 28 days of the first dose of study drug or anticipation of
             the need for major surgery during the course of study treatment

          -  Consumption of one or more of the following within 3 days prior to the first dose of
             study drug: Grapefruit or grapefruit products; Seville oranges including marmalade
             containing Seville oranges; Star fruit (carambola)

          -  Administration within 7 days prior first dose of study treatment of Steroid therapy
             for anti-neoplastic intent, Strong or moderate CYP3A inhibitors or Strong or moderate
             CYP3A inducers

          -  Need for current chronic corticosteroid therapy (> 10 mg of prednisone per day or an
             equivalent dose of other anti-inflammatory corticosteroids)

          -  Known infection with (human immunodeficiency virus) HIV or human T-cell leukemia virus
             1

          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
             (excluding fungal infections of nail beds) at study enrollment, or any major episode
             of infection requiring treatment with IV antibiotics or hospitalization (relating to
             the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day).

          -  Patients who are positive for HCV antibody must be negative for HCV by PCR to be
             eligible for study participation. Patients with a past or resolved hepatitis B virus
             (HBV) infection (defined as having a positive total HBcAb and negative hepatitis B
             surface antigen [HbsAg]) may be included if HBV DNA is undetectable. These patients
             must be willing to undergo monthly DNA testing

          -  Positive test results for hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV)
             antibody at screening

          -  Active HCV infection, defined as having a positive HCV antibody test at screening

          -  History of other malignancies within the past 5 years except for treated skin basal
             cell carcinoma, squamous cell carcinoma, non-malignant melanoma <= 1.0 mm without
             ulceration, localized thyroid cancer, or cervical carcinoma in-situ

          -  Administration of a live, attenuated vaccine within 4 weeks prior to initiation of
             study treatment or anticipation of need for such a vaccine during the study

          -  Cardiopulmonary dysfunction

          -  Other medical or psychiatric conditions that, in the opinion of the investigatory, may
             interfere with the patient's participation in the study

          -  Inability or unwillingness to swallow pills or receive intramuscular (IM) injections

          -  History of malabsorption syndrome or other condition that would interfere with enteral
             absorption

          -  History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or
             active bowel inflammation (e.g., diverticulitis)

          -  Concurrent hormone replacement therapy

          -  Inability to comply with study and follow-up procedures

          -  History or active cardiopulmonary dysfunction
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Sudden Death (SD) lasting >= 24 weeks
Time Frame:Randomization in patients with measurable disease at baseline through the end of study (2 years after the last patient is enrolled)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Randomization to the first occurrence of disease progression as determined by the investigator according to (RECIST v1.1 ) or death from any cause, until the end of study (2 years after the last patient is enrolled)
Safety Issue:
Description:(RECIST v1.1 ) Response Evaluation Criteria in Solid Tumors Version 1.1
Measure:Objective Response (OR)
Time Frame:Objective Response defined as Complete Response (CR) or Partial response (PR), as determined by the investigator according to RECIST v1.1 from Randomization of patient until end of the study (2 years after the last patient enrolled)
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:Time from first occurrence of a documented Objective response to the time of the first documented disease progression or death from any cause, whichever occurs first, until end of the study (2 years after the last patient enrolled)
Safety Issue:
Description:(as determined by the investigator according to RECIST v1.1)
Measure:Overall Survival (OS)
Time Frame:Randomization to death from any cause, through the end of study (2 years after the last patient enrolled)
Safety Issue:
Description:
Measure:Percentage of participants with adverse events
Time Frame:Baseline to end of study (2 years after the last patient enrolled)
Safety Issue:
Description:
Measure:Plasma concentration of Venetoxclax and fulvestrant
Time Frame:At pre-defined intervals from Cycle 1, Day 1, through end of treatment (2 years after the last patient enrolled).
Safety Issue:
Description:
Measure:Mean changes from baseline scores in functional disease/treatment-related symptoms and global health status health-related quality of life (GHS/HRQoL) by cycle
Time Frame:Baseline, cycle 1 day 1, and all subsequent cycles through at the end of treatment/discontinuation visit (2 years after the last patient enrolled)
Safety Issue:
Description:Mean and mean changes will be assessed by the scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
Measure:Change in baseline pain score as assessed by the pain scale of EORTC QLQ-C30
Time Frame:Baseline through end of study (2 years after the last patient enrolled)
Safety Issue:
Description:
Measure:Baseline BCL-2 protein levels as measured by International Council for Harmonisation (IHC) correlating with clinical response measures
Time Frame:Baseline through the end of study (2 years after the last patient enrolled)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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