Dose Escalation and Expansion Study of GSK525762 in Combination With Fulvestrant in Participants With Hormone Receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2-) Advanced or Metastatic Breast Cancer

NCT02964507 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2019732016-003074-40
• Study Type: interventional
• Target: 124
• Locations: 7 countries
• Sites: 38

Brief Summary

This is a combination Phase I and Phase II study, with an aim to evaluate the combination of GSK525762 and fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer, who have disease that has progressed after prior treatment with at least one line of endocrine therapy. The objectives of the study are to first identify, in open-label single-arm Phase I, a recommended Phase II dose of GSK525762 that may be combined safely with fulvestrant. Phase I will follow a modified toxicity probability interval (mTPI) design, and a sentinel group will be evaluated first for dose-limiting toxicity and further expanded to collect additional safety data. This will be followed by a double-blind, randomized controlled Phase II, to identify the clinical activity of the two study treatments when given in combination. The composition of Phase II will be selected at the end of Phase I.

Conditions

Neoplasms

Keywords

GSK525762; HR+/HER2- advanced or metastatic breast cancer; mTPI

Outcome Measures

Primary Outcomes (6)

• Phase I: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation such as important medical events according to medical or scientific judgement or is associated with liver injury and impaired liver function. Any other adverse event apart from SAE is considered as non-SAE.

  Up to 3 year and 8 months

• Phase I: Number of Participants With Dose Limiting Toxicities (DLTs)

  An event was considered DLT if it occurred within first 28 days of treatment and met one of following DLT criteria: Grade3 or greater neutropenia for \>=5 days, febrile neutropenia, Grade4 anemia of any duration, Grade4 thrombocytopenia of any duration or Grade3 thrombocytopenia with bleeding, alanine aminotransferase (ALT) \>3 times (x) upper limit of normal (ULN)+bilirubin \>=2x ULN (\>35 % direct) or ALT between 3-5xULN with bilirubin \<2xULN but with hepatitis symptoms or rash, Grade3 nausea,vomiting or diarrhea that did not improve within 72hour despite appropriate supportive treatment(s), Grade4 nausea,vomiting,or diarrhea, Grade3 hypertension (uncontrolled despite addition of upto 2 antihypertensive medications), Grade4 hypertension, other Grade3 or greater clinically significant non-hematologic toxicity (including QT duration corrected for heart rate by Fridericia's formula (QTcF), ejection fraction \<lower limit of normal (LLN) with an absolute decrease of \>10% from Baseline.

  Up to 28 days

• Phase I: Number of Participants With Dose Reductions and Dose Interruption/Delays

  Number of participants with dose reductions and dose interruption or delay due to any reason is presented.

  Up to 3 year and 8 months

• Phase I: Objective Response Rate-Investigator Assessment

  Objective Response Rate is defined as the percentage of participants who demonstrate a Best Response of confirmed complete response (CR) or partial response (PR), as assessed by the investigator per response evaluation criteria in solid tumors (RECIST) version (v) 1.1 criteria.

  Up to 3 year and 8 months

• Phase I: Plasma Concentration of GSK525762

  Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK525762.

  Day 1: Pre-dose, 0.5, 1, 3 hours on Weeks 1 and 3; Day 1: Pre-dose, 0.5-1, 4-8 hours on Week 5; Day 1: Pre-dose, 0.5-1 hour on Weeks 9, 17, 25

• Phase II: Progression Free Survival (PFS)

  PFS is defined as the time (in months) from the date of first dose until the date of first documented progressive disease (PD), as assessed by the investigator per RECIST v1.1 criteria, or date of death due to any cause, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions taking as a reference the smallest sum of diameters for this study.

  Up to 3 year and 8 months

Secondary Outcomes (11)

• Phase I: Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment

  Up to 4 year and 4 months

• Phase I: Disease Control Rate (DCR)

  Up to 3 year and 8 months

• Phase I: Duration of Response (DoR)

  Up to 3 year and 8 months

• Phase I: Progression-free Survival (PFS)

  Up to 3 year and 8 months

• Phase I: Plasma Concentration of GSK3529246

  Day 1: Pre-dose, 0.5, 1, 3 hours on Weeks 1 and 3; Day 1: Pre-dose, 0.5-1, 4-8 hours on Week 5, Day 1: pre-dose, 0.5-1 hour on Weeks 9, 17, 25

Other Outcomes (2)

• Phase I: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) Until End of the Study

  Up to 4 year and 4 months

• Phase I: Number of Participants With Dose Reductions and Dose Interruption/Delays Until End of the Study

  Up to 4 year and 4 months

Study Arms (3)

GSK525762 + Fulvestrant (Phase I)

EXPERIMENTAL

Drug: GSK525762; Drug: Fulvestrant

GSK525762 + Fulvestrant (Phase II)

EXPERIMENTAL

Drug: GSK525762; Drug: Fulvestrant

Placebo + Fulvestrant (Phase II)

PLACEBO COMPARATOR

Drug: Placebo; Drug: Fulvestrant

Interventions

GSK525762 DRUG

GSK525762 will be administered.

GSK525762 + Fulvestrant (Phase I); GSK525762 + Fulvestrant (Phase II)

Placebo DRUG

Placebo will be administered.

Placebo + Fulvestrant (Phase II)

Fulvestrant DRUG

Fulvestrant will be administered.

GSK525762 + Fulvestrant (Phase I); GSK525762 + Fulvestrant (Phase II); Placebo + Fulvestrant (Phase II)

Eligibility Criteria

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

You may qualify if:

• Written informed consent provided.
• Females 18 years old and greater (at the time of written consent)
• Histologically or cytologically confirmed diagnosis of advanced or metastatic adenocarcinoma of the breast.
• Documentation of estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive tumor (\>=1% positive stained tumor cell nuclei) based on local testing of the most recent tumor biopsy, using an assay consistent with local standards.
• Documentation of HER2-negative tumor based on local testing of the most recent tumor biopsy as per most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. At the time of writing, HER2-negative tumor is defined as immunohistochemistry (IHC) score of 0 or 1+, or negative by in situ hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio \<2 or for single probe assessment of an average HER2 copy number \<4.
• Provision of mandatory screening fresh tumor biopsy sample during the screening period: a. Screening biopsy can be waived if a biopsy was collected within 3 months prior to first dose of study drug and was collected after the last anti-cancer treatment before coming into this study; b. Participants with inaccessible site of biopsy or who have a significant medical risk of obtaining the biopsy should be discussed with the Medical Monitor if they can qualify; c. Bone biopsies are not acceptable. Biopsies should be obtained from bone with metastatic soft-tissue component. Participants with bone only disease may be enrolled upon review by Medical Monitor.
• History of prior therapy that satisfies one of the following criteria: a. Aromatase inhibitor (AI) failures: Disease that relapsed during treatment or within 12 months of completion of adjuvant therapy with an AI, OR disease that progressed during treatment with an AI for advanced/metastatic disease. Prior ovarian suppression and/or tamoxifen are allowed as long as other criteria are met; b. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus AI failures: Disease that progressed on a CDK4/6 inhibitor plus AI, for advanced/metastatic disease with a minimum duration of treatment of 12 months (\>=12 months) with CDK4/6 inhibitor plus AI. Participants with either measurable disease or bone only disease are allowed. Prior ovarian suppression and/or tamoxifen are allowed as long as other criteria are met.
• Documented progression on last line of systemic anti-cancer therapy with CDK4/6 inhibitor plus AI is required.
• Any menopausal status.
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria is required except for participants with bone only disease.
• All prior treatment- related toxicities must be National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 \<=Grade 1 (except alopecia (permitted at any grade) and peripheral neuropathy (permitted at \<=Grade 2) at the time of treatment allocation.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1.
• Adequate organ function.
• Able to swallow and retain orally administered medication.
• A female participant is eligible to participate if she is of: i) Non-childbearing potential. ii) Child-bearing potential and agrees to use one of the contraception methods. iii) Negative serum pregnancy test \<=7 days prior to first study drug dose. iv) Female participants who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for at least 28 days following the last dose of study treatment.

You may not qualify if:

• Prior therapy with any Bromodomain and extra-terminal (BET) inhibitor, any selective estrogen receptor degrader (SERD) including fulvestrant, or inhibitors of the Phosphoinositide-3-kinase (PI3K)/ serine/threonine-specific protein kinase (AKT)/Mammalian Target of Rapamycin (mTOR) pathway.
• Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease.
• More than or equal to 3 lines of systemic anti-cancer therapy in the advanced or metastatic setting.
• Recent prior therapy, defined as: a. Any investigational or approved non-biologic anti-cancer drug within 14 days or five half-life (whichever is greater) prior to the first dose of GSK525762 and fulvestrant. b. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK525762 and fulvestrant c. Any anti-cancer biologic agents within 42 days prior to the first dose of GSK525762 and fulvestrant. d. Any radiotherapy within 14 days prior to the first dose of GSK525762 and fulvestrant. If the participant received radiotherapy \<90 days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response.
• e. Any major surgery within 28 days prior to the first dose of GSK525762 and fulvestrant
• Concomitant active malignancy other than HR+/HER2- breast cancer
• Therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin \[LMWH\], or novel oral anticoagulants) must be discontinued and coagulation parameters must be normalized prior to the first dose of GSK525762 and fulvestrant. Prophylactic anticoagulation, with low doses (per standard practice) of agents such as LMWH, direct thrombin inhibitors, or factor Xa inhibitors is permitted.
• Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK525762 and fulvestrant. This includes medications with significant risk of Torsades de pointes as well as those that are potent inducers or inhibitors of Cytochrome P3A4 (CYP3A4) enzymes.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator. a) Systolic blood pressure higher than 150 millimeters of mercury (mmHg) or diastolic blood pressure higher than 90 mmHg found on 2 separate occasions separated by 1 week, despite adequate therapy, will be defined as uncontrolled hypertension. b) Uncontrolled diabetes mellitus (despite therapeutic; compliance to intervention) as defined by a hemoglobin A1c (HbA1c) level more than 8% and/or occurrence of more than two episodes of ketoacidosis in the 12 months prior to the first dose of study drug.
• Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term including participants with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50 percent (%) of liver involvement in metastases.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
• Cardiac abnormalities as evidenced by any of the following: Baseline QT interval corrected by Fridericia's formula (QTcF) interval \>=480 milliseconds (msec); Clinically significant conduction abnormalities or arrhythmias; Presence of cardiac pacemaker or defibrillator with a paced ventricular rhythm limiting electrocardiogram analysis; History or evidence of current \>=Class II congestive heart failure as defined by New York Heart Association (NYHA); History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months. Participants with a history of stent placement requiring ongoing antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be permitted to enroll; Clinically significant cardiomegaly, ventricular hypertrophy, or cardiomyopathy.
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment).
• Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening.
• History of known human immunodeficiency virus (HIV) infection.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (38)

GSK Investigational Site

Birmingham, Alabama, 35249, United States

Location

GSK Investigational Site

Gilbert, Arizona, 85234, United States

Location

GSK Investigational Site

Scottsdale, Arizona, 85259, United States

Location

GSK Investigational Site

San Diego, California, 92123, United States

Location

GSK Investigational Site

Plantation, Florida, 33324, United States

Location

GSK Investigational Site

Chicago, Illinois, 60611, United States

Location

GSK Investigational Site

New Orleans, Louisiana, 70121, United States

Location

GSK Investigational Site

Rochester, Minnesota, 55905, United States

Location

GSK Investigational Site

Kansas City, Missouri, 64111, United States

Location

GSK Investigational Site

St Louis, Missouri, 63110, United States

Location

GSK Investigational Site

The Bronx, New York, 10461, United States

Location

GSK Investigational Site

White Plains, New York, 10601, United States

Location

GSK Investigational Site

Providence, Rhode Island, 02903, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Seattle, Washington, 98101, United States

Location

GSK Investigational Site

Port Macquarie, New South Wales, 2444, Australia

Location

GSK Investigational Site

Bedford Park, South Australia, 5042, Australia

Location

GSK Investigational Site

Heidelberg, Victoria, 3084, Australia

Location

GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2L 4M1, Canada

Location

GSK Investigational Site

Montreal, Quebec, H3T 1E2, Canada

Location

GSK Investigational Site

Québec, Quebec, G1S 4L8, Canada

Location

GSK Investigational Site

Bordeaux, 33076, France

Location

GSK Investigational Site

Saint-Herblain, 44805, France

Location

GSK Investigational Site

Gyeonggi-do, 410-769, South Korea

Location

GSK Investigational Site

Seoul, 120-752, South Korea

Location

GSK Investigational Site

Seoul, 135-710, South Korea

Location

GSK Investigational Site

Seoul, 138-736, South Korea

Location

GSK Investigational Site

A Coruña, 15006, Spain

Location

GSK Investigational Site

Barcelona, 8035, Spain

Location

GSK Investigational Site

Lleida, 25198, Spain

Location

GSK Investigational Site

Manchester, Lancashire, M20 4BX, United Kingdom

Location

GSK Investigational Site

Northwood, Middlesex, HA6 2RN, United Kingdom

Location

GSK Investigational Site

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

GSK Investigational Site

Glasgow, G12 OYN, United Kingdom

Location

GSK Investigational Site

London, EC1M 6BQ, United Kingdom

Location

GSK Investigational Site

London, NW1 2PG, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms; Breast Neoplasms

Interventions

molibresib; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; 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: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  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: November 12, 2016
• First Posted: November 16, 2016
• Study Start: September 26, 2019
• Primary Completion: September 29, 2020
• Study Completion: July 19, 2021
• Last Updated: August 29, 2024
• Results First Posted: January 27, 2022

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Anonymized IPD is made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.

Locations

GB (6); US (15); CA (5); FR (2); AU (3); ES (3); KR (4)