Clinical Trials /

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

NCT02964507

Description:

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. Approximately, up to 140 subjects and 154 subjects will receive study treatment in Phase I and Phase II respectively. A completed subject will be one who is followed until death.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation and Expansion Study of GSK525762 in Combination With Fulvestrant in Subjects With Estrogen Receptor Positive (ER+) Breast Cancer
  • Official Title: A Phase I/II Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Combination With Fulvestrant in Subjects With ER+ Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 201973
  • NCT ID: NCT02964507

Conditions

  • Cancer

Interventions

DrugSynonymsArms
GSK525762GSK525762 + Fulvestrant (Phase I)
PlaceboPlacebo + Fulvestrant (Phase II)
FulvestrantGSK525762 + Fulvestrant (Phase I)

Purpose

This is a combination Phase I and Phase II study, with an aim to evaluate the combination of GSK525762 and fulvestrant in women with advanced or metastatic ER+ 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.

Approximately, up to 140 subjects and 154 subjects will receive study treatment in Phase I and Phase II respectively. A completed subject will be one who is followed until death.

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
GSK525762 + Fulvestrant (Phase I)ExperimentalIn Phase I, all subjects will receive treatment with GSK525762 in combination with fulvestrant. Dosing will be continued until unacceptable toxicity, progression of disease, death, or withdrawal of consent.
  • GSK525762
    • Fulvestrant
GSK525762 + Fulvestrant (Phase II)ExperimentalSubjects will receive treatment with GSK525762 in combination with fulvestrant, at a GSK525762-dose level selected from Phase I. Dosing will be continued until unacceptable toxicity, progression of disease, death, or withdrawal of consent.
  • GSK525762
    • Fulvestrant
Placebo + Fulvestrant (Phase II)Placebo ComparatorIn Phase II, subjects will receive treatment with placebo in combination with fulvestrant. Dosing will be continued until unacceptable toxicity, progression of disease, death, or withdrawal of consent.
    • Placebo
    • Fulvestrant

Eligibility Criteria

Inclusion Criteria:

- Females 18 years old and greater with histologically or cytologically confirmed diagnosis of advanced or metastatic adenocarcinoma of the breast.

- History of prior therapy that satisfies one of the following criteria:

1. Disease that progressed during treatment or within 12 months of completion of adjuvant therapy with tamoxifen and/or an aromatase inhibitor (AI).

2. Disease that progressed during treatment or within 1 month after the end of treatment with prior tamoxifen, AI, or cyclin-dependent kinase (CDK) 4/6 inhibitor plus letrozole, for advanced/metastatic disease.

- Documentation of ER-positive and/or progesterone receptor (PR)-positive tumor.

- Documentation of human epidermal growth factor receptor 2 (HER2)-negative tumor.

- Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST)

- Adequate organ function as per pre-defined hematologic, hepatic, renal, and cardiac criteria.

Exclusion Criteria:

- Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease, or disease which has progressed despite prior fulvestrant therapy.

- Concomitant active malignancy other than ER+ breast cancer.

- Therapeutic-dose anticoagulation must be discontinued and coagulation parameters must be normalized prior to the first dose of GSK525762 and fulvestrant.

- Evidence of severe or uncontrolled systemic diseases (example, unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes).

- Subjects with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term including subjects with massive uncontrolled effusions, pulmonary lymphangitis, and over 50% of liver involvement in metastases.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.

- Cardiac abnormalities

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

Primary Outcome Measures

Measure:Phase I: Number of subjects with adverse events (AE) and serious adverse events (SAE), for the determination of recommended Phase II dose of GSK525762
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:ORR is defined as complete response (CR) rate plus partial response (PR) rate.

Secondary Outcome Measures

Measure:Phase I: Number of subjects with AEs or SAEs, as a measure of safety and tolerability
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects with dose reductions or delays, as a measure of safety and tolerability
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects withdrawn due to toxicity
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects with abnormality in laboratory parameters
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects with abnormality in vital signs
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects with abnormality in electrocardiogram (ECG)
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects with abnormality in any cardiotoxicity parameters
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Number of subjects with abnormality in gastrointestinal parameters
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Disease control rate (DCR)
Time Frame:From Day 1 until end of treatment (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Duration of response
Time Frame:From Day 1 until disease progression or death (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: PFS
Time Frame:From Day 1 until disease progression or death (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Time to progression (TTP)
Time Frame:From Day 1 until disease progression or death (approximately 15 months)
Safety Issue:
Description:
Measure:Phase I: Plasma concentration of GSK525762 and its metabolites, as a measure of drug exposure
Time Frame:Day 1 of Weeks 1, 3, 5, 9, 16, and 24
Safety Issue:
Description:
Measure:Phase I: Plasma concentration of fulvestrant, as a measure of drug exposure
Time Frame:Day 1 of Weeks 1, 3, 5, 9, 16, and 24
Safety Issue:
Description:
Measure:Phase I: Correlation between ESR1 mutations and clinical response, determined by targeted sequencing of tumor tissue
Time Frame:Over a period of approximately 15 months
Safety Issue:
Description:
Measure:Phase II: Overall Survival (OS)
Time Frame:From Day 1 until death (approximately 16 months)
Safety Issue:
Description:
Measure:Phase II: TTP
Time Frame:From Day 1 until disease progression or death (approximately 16 months)
Safety Issue:
Description:
Measure:Phase II: ORR
Time Frame:From Day 1 until end of treatment (approximately 16 months)
Safety Issue:
Description:
Measure:Phase II: DCR
Time Frame:From Day 1 until end of treatment (approximately 16 months)
Safety Issue:
Description:
Measure:Phase II: Plasma concentration of GSK525762 and its metabolites, as a measure of drug exposure
Time Frame:Day 1 of Weeks 1, 5, 9, 16, and 24
Safety Issue:
Description:
Measure:Phase II: Plasma concentration of fulvestrant, as a measure of drug exposure
Time Frame:Day 1 of Weeks 1, 5, 9, 16, and 24
Safety Issue:
Description:
Measure:Phase II: Correlation between ESR1 mutations and clinical response, determined by targeted sequencing of tumor tissue
Time Frame:Screening, and (optionally) at end of treatment (approximately 16 months)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • GSK525762
  • ER+ breast cancer
  • mTPI

Last Updated

January 16, 2017