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

NCT02983604 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GS-US-350-19372016-002365-63
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 6

Brief Summary

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 and to determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose of GS-5829 in combination with fulvestrant in women with advanced estrogen receptor positive, HER2-negative (ER+/HER2-) breast cancer. The primary objective of the Randomized Phase 2 Dose Expansion portion of this study is 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.

Conditions

Advanced Estrogen Receptor Positive HER2- Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Phase 1b Dose Escalation: Number of Participants Experiencing Dose Limiting Toxicities (DLTs) Through Day 28 at Each Dose Level of GS-5829

  A DLT was a toxicity as defined below: * Grade ≥ 4 neutropenia * Grade ≥ 3 neutropenia with fever * Grade ≥ 3 thrombocytopenia * Grade ≥ 2 bleeding (e.g., gastrointestinal, respiratory, epistaxis, purpura) * Grade ≥ 3 or higher non-hematologic toxicity, except: * Grade 3 nausea or emesis with maximum duration of 48 hours on adequate medical therapy * Grade 3 diarrhea which persists for \< 72 hours in the absence of adequate medical therapy * Grade ≥ 2 non-hematologic treatment-emergent adverse event (TEAE) that in the opinion of the investigator is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk * Treatment interruption of ≥ 7 days due to unresolved toxicity * Grade 3 or Grade 4 elevation in aspartate transaminase (AST) or alanine transaminase (ALT) associated with a Grade 2 elevation in bilirubin that is at least possibly related to study drug

  Baseline up to 28 days

• Randomized Phase 2 Dose Expansion: Progression-Free Survival

  Progression-Free Survival (PFS) was defined as the interval from date of randomization to the earlier of the first documented confirmed disease progression or death from any cause.

  Baseline up to 2 years

Secondary Outcomes (6)

• Phase 1b Dose Escalation: Pharmacokinetic (PK) Parameter: Cmax of GS-5829

  Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Days 1 and 15

• Phase 1b Dose Escalation: PK Parameter: AUCtau of GS-5829

  Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Day 15

• 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

  Baseline up to 2 years

• Randomized Phase 2 Dose Expansion: Overall Response Rate

  Baseline up to 2 years

• Randomized Phase 2 Dose Expansion: Clinical Benefit Rate

  Baseline up to 2 years

Study Arms (4)

GS-5829 + exemestane (Phase 1b)

EXPERIMENTAL

Participants will be sequentially enrolled at progressively higher dose levels of GS-5829 (up to 9 mg) in combination with exemestane and may continue with treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.

Drug: GS-5829; Drug: Exemestane

GS-5829 + fulvestrant (Phase 1b)

EXPERIMENTAL

Participants will be sequentially enrolled at progressively higher dose levels of GS-5829 (up to 9 mg) in combination with fulvestrant and may continue with treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.

Drug: GS-5829; Drug: Fulvestrant

GS-5829 + fulvestrant (Phase 2)

EXPERIMENTAL

Participants will receive GS-5829 (dose determined from Phase 1b) + fulvestrant until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.

Drug: GS-5829; Drug: Fulvestrant

Fulvestrant (Phase 2)

ACTIVE COMPARATOR

Participants will receive fulvestrant alone until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever comes first.

Drug: Fulvestrant

Interventions

GS-5829 DRUG

Tablet(s) administered orally once daily

GS-5829 + exemestane (Phase 1b); GS-5829 + fulvestrant (Phase 1b); GS-5829 + fulvestrant (Phase 2)

Exemestane DRUG

25 mg tablet administered orally once daily (or in accordance with locally approved labeling)

Also known as: Aromasin®

GS-5829 + exemestane (Phase 1b)

Fulvestrant DRUG

Administered every 28 days (± 3 days) intramuscularly in accordance with locally approved labeling Participants initiating fulvestrant on Cycle 1 Day 1 and have not received any prior dose of fulvestrant will receive a single additional dose of fulvestrant on Cycle 1 Day 15.

Also known as: Faslodex®

Fulvestrant (Phase 2); GS-5829 + fulvestrant (Phase 1b); GS-5829 + fulvestrant (Phase 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.
• Randomized Phase 2 Dose Expansion - Individuals may have disease progression during treatment or within 12 months of completion of endocrine therapy (tamoxifen, and/or AI) in the adjuvant setting, or disease progression during treatment with endocrine therapy (tamoxifen, AI or CDK4/6 inhibitor plus AI) for advanced/metastatic disease. Individuals may have had unlimited prior hormonal therapy, but must be naive to fulvestrant in the metastatic setting. A total of 2 prior chemotherapies are allowed, however, only one for metastatic disease is permitted.
• 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-, pre- or peri-menopausal women 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 Cycle 1 Day 1 (C1D1). 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:

You may not qualify if:

• 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 (Note: if treated and stable at least 6 months prior to enrollment, individual is eligible).
• Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, active or chronic bleeding event within 28 days prior to C1D1, 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 C1D1
• 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, antibody therapy, molecular targeted therapy) within 21 days or 5 half-lives whichever is longer, of C1D1 (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
• Known hypersensitivity to the study drugs (GS 5829, fulvestrant or exemestane), the metabolites, or formulation excipients
• 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/antiplatelet therapy within 7 days of C1D1, including acetylsalicylic acid, low molecular weight heparin, or warfarin

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (6)

Stanford Women's Cancer Center

Stanford, California, 94305, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Allina Health, Virginia Piper Cancer Institute

Minneapolis, Minnesota, 55407, United States

Location

The Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Baylor University Medical Center

Houston, Texas, 77030, United States

Location

Medical Oncology Associates, PS (dba Summit Cancer Centers)

Spokane, Washington, 99208, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

exemestane; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2016
• First Posted: December 6, 2016
• Study Start: January 10, 2017
• Primary Completion: July 19, 2018
• Study Completion: July 19, 2018
• Last Updated: August 7, 2019
• Results First Posted: August 7, 2019

Record last verified: 2019-07

Locations

US (6)