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GS-5829 in Combination With Fulvestrant or Exemestane in Women With Advanced Estrogen Receptor Positive, HER2 Negative-Breast Cancer

NCT02983604

Description:

The primary objectives of the Phase 1b Dose Escalation part of this study are to characterize the safety and tolerability of GS-5829 in combination with exemestane or fulvestrant in women with advanced estrogen receptor positive Her2-negative (ER+/HER2-) breast cancer and to determine the maximum tolerated dose (MTD) (if not already determined) or the recommended dose for the Phase 2 part of this study. The primary objectives of the Randomized Phase 2 Dose Expansion portion of this study are to evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant alone in women with advanced ER+/HER2- breast cancer. This study was terminated early and the Phase 2 portion of the study was not conducted.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: GS-5829 in Combination With Exemestane or Fulvestrant Comparing With Exemestane or Fulvestrant Alone in Women With Advanced Estrogen Receptor Positive HER2- Breast Cancer
  • Official Title: A Phase 1b Study Followed by an Open Label, Parallel, Randomized Phase 2 Study Evaluating the Safety, Tolerability and Efficacy of GS-5829 in Combination With Exemestane or Fulvestrant Comparing With Exemestane or Fulvestrant Alone in Subjects With Advanced Estrogen Receptor Positive HER2- Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: GS-US-350-1937
  • SECONDARY ID: 2016-002365-63
  • NCT ID: NCT02983604

Conditions

  • Advanced Estrogen Receptor Positive HER2- Breast Cancer

Interventions

DrugSynonymsArms
GS-5829GS-5829 + exemestane (Phase 1b)
ExemestaneAromasin®GS-5829 + exemestane (Phase 1b)
FulvestrantFaslodex®GS-5829 + fulvestrant (Phase 1b)

Purpose

The primary objectives of the Phase 1b Dose Escalation part of this study are to characterize the safety and tolerability of GS-5829 in combination with exemestane or fulvestrant in women with advanced estrogen receptor positive Her2-negative (ER+/HER2-) breast cancer and to determine the maximum tolerated dose (MTD) (if not already determined) or the recommended dose for the Phase 2 part of this study.

The primary objectives of the Randomized Phase 2 Dose Expansion portion of this study are to evaluate the efficacy of GS-5829 in combination with exemestane or fulvestrant compared to exemestane or fulvestrant alone in women with advanced ER+/HER2- breast cancer.

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
GS-5829 + exemestane (Phase 1b)ExperimentalParticipants will be sequentially enrolled at progressively higher dose levels of GS-5829 in combination with exemestane and may continue with treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.
  • GS-5829
  • Exemestane
    GS-5829 + fulvestrant (Phase 1b)ExperimentalParticipants will be sequentially enrolled at progressively higher dose levels of GS-5829 in combination with fulvestrant and may continue with treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.
    • GS-5829
      • Fulvestrant
    GS-5829 + exemestane (Phase 2)ExperimentalParticipants will receive GS-5829 (dose determined from Phase 1b) + exemestane until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.
    • GS-5829
    • Exemestane
      Exemestane (Phase 2)Active ComparatorParticipants will receive exemestane alone until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.
        • Exemestane
        GS-5829 + fulvestrant (Phase 2)ExperimentalParticipants will receive GS-5829 (dose determined from Phase 1b) + fulvestrant until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.
        • GS-5829
          • Fulvestrant
        Fulvestrant (Phase 2)Active ComparatorParticipants will receive fulvestrant alone until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.
            • Fulvestrant

        Eligibility Criteria

        Key Inclusion Criteria:

        - Histologically or cytologically confirmed breast cancer with evidence of metastatic or locally advanced disease not amenable to resection or radiation therapy with curative intent and who have progressed during treatment with at least one prior hormonal therapy. Note: In referring to prior hormonal therapy; targeted therapies, such as palbociclib and/or everolimus or investigative targeted therapies which were administered as part of a prior hormonal therapy regimen are allowed after the washout period has been reached.

        - Phase 1b Dose Escalation - Individuals may have had unlimited prior hormonal therapy and a total of 2 prior chemotherapy regimens (adjuvant chemotherapy is considered 1 regimen). Individuals may have progressed on fulvestrant or exemestane as a single agent

        - Randomized Phase 2 Dose Expansion - Individuals may have had unlimited prior hormonal therapy, only one adjuvant chemotherapy is permitted (no prior chemotherapy for metastatic disease is allowed). Individuals enrolling in Group 1 must be exemestane naïve and individuals enrolling in Group 2 must be fulvestrant naïve. If an individual is naive to both exemestane and fulvestrant, it is the investigator's decision for which Group to enroll

        - Documentation of ER positive (≥ 1% positive stained cells by local standards) based on the most recent tumor biopsy, unless bone-only disease

        - Documented HER2-negative tumor based on local testing on most recent tumor biopsy (immunohistochemistry score 0/1+ or negative by in situ hybridization HER2/CP17 ratio < 2 or for single probe assessment HER2 copy number < 4)

        - Post-menopausal individuals considered to be in the post-menopausal state as defined by one of the following:

        - Age ≥ 60 years

        - Age < 60 years and cessation of regular menses for at least 12 consecutive months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and serum estradiol and follicle-stimulating hormone (FSH) level within the post-menopausal range

        - Prior bilateral oophorectomy

        - Pre-/peri-menopausal women can be enrolled if amenable to be treated with the luteinizing-hormone releasing hormone (LHRH) agonist, goserelin. Individuals must have commenced treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to first dose of study drug. If individuals have received an alternative LHRH agonist prior to study entry, they must switch to goserelin on or before Cycle 1 Day 1 (C1D1) for the duration of the study

        - Measurable disease defined per RECIST v. 1.1, or bone-only disease must have a lytic or mixed lytic blastic lesion that can be accurately assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Individuals with bone-only disease and blastic-only metastases are not eligible

        - All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of study drug dosing (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity [Grade 1 or 2 permitted])

        - Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1

        - Life expectancy of ≥ 3 months, in the opinion of the investigator

        - Adequate organ function defined as follows:

        - Hematologic: Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (without platelet transfusion or any granulocytic growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit)

        - Hepatic: aspartate transaminase (AST) / alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN); total or conjugated bilirubin ≤ 1.5 x ULN

        - Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min as calculated by the Cockroft-Gault method

        - Coagulation: International Normalized Ratio (INR) ≤ 1.2

        - Negative serum pregnancy test

        - Females of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in the study protocol

        - Females who are nursing must agree to discontinue nursing before the first dose of GS-5829

        - Able and willing to provide written informed consent to participate in the study

        Key Exclusion Criteria:

        - History or evidence of clinically significant disorder, condition, or disease that, in the opinion of the investigator or the Gilead medical monitor would pose a risk to individual safety or interfere with the study evaluations, procedures, or completion

        - Known brain metastasis or leptomeningeal disease

        - Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, active or chronic bleeding event within 28 days prior to first dose of study drug, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician

        - Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of C1D1

        - Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e., larger than what is required for placement of central venous access, percutaneous feeding tube) within 28 days of the first dose of study drug

        - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of GS-5829, including any unresolved nausea, vomiting, or diarrhea that is Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1

        - Minor surgical procedure(s) within 7 days of enrollment or randomization, or not yet recovered from prior surgery (placement of central venous access device, fine needle aspiration, or endoscopic biliary stent ≥ 1 day before enrollment or randomization is acceptable)

        - History of a concurrent or second malignancy, except for: adequately treated local basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; adequately treated Stage 1 or 2 cancer currently in complete remission; any other cancer that has been in complete remission for ≥ 5 years

        - Anti-tumor therapy (chemotherapy, chemoradiation, radiation, molecular targeted therapy) within 21 days or 5 half-lives whichever is longer, of study drug dosing (6 weeks for nitrosoureas, mitomycin C, or molecular agents with t1/2 > 10 days); 5 half-lives of any investigational drug; concurrent use of goserelin for pre-/peri-menopausal breast cancer and exemestane or fulvestrant per the protocol are permitted

        - History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 470 ms). Individuals who screen fail due to this criterion are not eligible to be re-screened

        - Prior exposure to any bromodomain (BET) inhibitors

        - Immunotherapy within 6 months of C1D1

        - Evidence of bleeding diathesis or clinically significant bleeding, within 28 days of C1D1 or history of hemoptysis of > 2.5 mL/1 teaspoon within 6 months of C1D1

        - Anticoagulation therapy within 7 days of C1D1, including acetylsalicylic acid, low molecular weight heparin, or warfarin

        - Known human immunodeficiency virus (HIV) infection

        - Hepatitis B surface Antigen (HBsAg) positive

        - Hepatitis C virus (HCV) antibody positive with HCV RNA positive

        - Use of moderate/strong cytochrome P450 (CYP)3A4 inhibitors or moderate/strong CYP3A4 inducers within 2 weeks prior to the first dose of study drug

        - History of high grade esophageal or gastric varices

        Note: Other protocol defined Inclusion/Exclusion criteria may apply.

        Maximum Eligible Age:N/A
        Minimum Eligible Age:18 Years
        Eligible Gender:Female
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Phase 1b Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) Through Day 28 at Each Dose Level of GS-5829
        Time Frame:Up to 28 days
        Safety Issue:
        Description:Progression-Free Survival (PFS) is defined as the interval from date of randomization to the earlier of the first documented confirmed disease progression or death from any cause.

        Secondary Outcome Measures

        Measure:Phase 1b Dose Escalation: Pharmacokinetic (PK) Parameter: Cmax of GS-5829
        Time Frame:Predose and up to 24 hours postdose
        Safety Issue:
        Description:Cmax is defined as the maximum observed concentration of drug.
        Measure:Phase 1b Dose Escalation: PK Parameter: AUCtau of GS-5829
        Time Frame:Predose and up to 24 hours postdose
        Safety Issue:
        Description:AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
        Measure:Randomized Phase 2 Dose Expansion: Overall Safety Profile as Assessed by the Percentage of Participants Experiencing Any Adverse Events (AEs), Grade 3 or 4 AEs, Treatment-Related AEs, or Abnormalities in Laboratory Tests or Electrocardiograms
        Time Frame:Up to 2 years
        Safety Issue:
        Description:
        Measure:Randomized Phase 2 Dose Expansion: Overall Response Rate
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Overall response rate (ORR) is defined as the proportion of participants who achieve complete response (CR) or partial response (PR), based on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 study progression criteria.
        Measure:Randomized Phase 2 Dose Expansion: Clinical Benefit Rate
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Clinical benefit rate (CBR) is defined as the proportion of participants who achieve CR, PR, or SD that lasts for > 24 weeks based on RECIST v. 1.1 study progression criteria.
        Measure:Randomized Phase 2 Dose Expansion: Overall Survival
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Overall survival is defined as the interval from date of randomization to date of death from any cause.

        Details

        Phase:Phase 1/Phase 2
        Primary Purpose:Interventional
        Overall Status:Recruiting
        Lead Sponsor:Gilead Sciences

        Trial Keywords

        • Exemestane
        • Aromasin
        • Fulvestrant
        • Faslodex
        • Breast Cancer,
        • HER 2-
        • Estrogen receptor positive

        Last Updated

        January 12, 2017