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A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer

NCT03332797

Description:

This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent and in combination with palbociclib and/or luteinizing hormone-releasing hormone (LHRH) agonist in participants with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 [HER2]-negative) breast cancer.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer
  • Official Title: A Phase Ia/Ib, Multicenter, Open-Label, Dose Escalation, Dose Expansion Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC-9545 Alone or in Combination With Palbociclib and/or LHRH Agonist in Patients With Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: GO39932
  • SECONDARY ID: 2017-002083-41
  • NCT ID: NCT03332797

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
GDC-9545Giredestrant, RO7197597, RG6171Dose Escalation: Cohort B0: GDC-9545 + Palbociclib
PalbociclibDose Escalation: Cohort B0: GDC-9545 + Palbociclib
LHRH AgonistDose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH

Purpose

This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent and in combination with palbociclib and/or luteinizing hormone-releasing hormone (LHRH) agonist in participants with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 [HER2]-negative) breast cancer.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation: GDC-9545ExperimentalDuring dose escalation, postmenopausal participants will be assigned sequentially to escalating doses of GDC-9545, up to the maximum tolerated dose (MTD) or maximum administered dose (MAD).
  • GDC-9545
Dose Escalation: Cohort B0: GDC-9545 + PalbociclibExperimentalGDC-9545 will be administered to postmenopausal participants, at a dose lower than the MTD or MAD determined in single-agent dose escalation, in combination with the label-recommended dose of palbociclib.
  • GDC-9545
  • Palbociclib
Dose Expansion: Cohort A1: GDC-9545 Dose 1ExperimentalGDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 1).
  • GDC-9545
Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRHExperimentalGDC-9545 will be administered to pre- or perimenopausal participants at a dose that is less than or equal to the MTD/MAD (Dose 1) in combination with an approved LHRH agonist.
  • GDC-9545
  • LHRH Agonist
Dose Expansion: Cohort A3: GDC-9545 Dose 2ExperimentalGDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 2).
  • GDC-9545
Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRHExperimentalGDC-9545 will be administered to pre- or perimenopausal participants at a dose that is less than or equal to the MTD/MAD (Dose 2) in combination with an LHRH agonist.
  • GDC-9545
  • LHRH Agonist
Dose Expansion: Cohort A5: GDC-9545 Dose 3ExperimentalGDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 3).
  • GDC-9545
Dose Expansion: Cohort B1: GDC-9545 + PalbociclibExperimentalGDC-9545 will be administered to postmenopausal participants, at a dose that is less than or equal to the MTD/MAD, in combination with the label-recommended dose of palbociclib.
  • GDC-9545
  • Palbociclib
Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRHExperimentalGDC-9545 will be administered to pre- or perimenopausal participants, at a dose that is less than or equal to the MTD/MAD, in combination with the label-recommended dose of palbociclib and an approved LHRH agonist.
  • GDC-9545
  • Palbociclib
  • LHRH Agonist
Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- PalbociclibExperimentalGDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2) as a single agent for 14 days, followed by treatment with either GDC-9545 (Dose 2) plus palbociclib or GDC-9545 (Dose 2) alone for the duration of the study, as determined by the investigator.
  • GDC-9545
  • Palbociclib
Dose Expansion: Cohort C2: GDC-9545 Dose 2 + PalbociclibExperimentalGDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2), in combination with the label-recommended dose of palbociclib.
  • GDC-9545
  • Palbociclib
Dose Expansion: Cohort X: GDC-9545 Dose 3ExperimentalGDC-9545 will be administered at a pre-defined dose level (Dose 3) to postmenopausal participants currently receiving clinical benefit with GDC-0927 or GDC-0810 on Studies GO29656 (NCT02316509) or GO29642 (NCT01823835), respectively, upon completion of their studies.
  • GDC-9545

Eligibility Criteria

        Inclusion Criteria for Dose Escalation:

          -  Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with
             evidence of either locally recurrent disease not amenable to resection or radiation
             therapy with curative intent or with metastatic disease

          -  Estrogen receptor (ER)-positive tumor

          -  Human epidermal growth factor receptor 2 (HER2)-negative breast cancer as per local
             laboratory testing

          -  Measurable disease, or evaluable bone disease; that is, bone lesions that are lytic or
             mixed (lytic + sclerotic) in the absence of measurable lesion

          -  Required paired pre- and on-treatment tumor biopsies for participants with metastases
             that are safely accessible as determined by the investigator

          -  Advanced or metastatic ER-positive/HER2-negative breast cancer that has recurred or
             progressed while being treated with adjuvant endocrine therapy for a duration of at
             least 24 months and/or endocrine therapy in the incurable, locally advanced, or
             metastatic setting and derived a clinical benefit from therapy (i.e., tumor response
             or stable disease for at least 6 months)

          -  No more than 2 prior lines of treatment for advanced or metastatic breast cancer

          -  Greater than or equal to (≥)2 weeks must have elapsed from the use of any other
             endocrine, targeted therapy or chemotherapy

          -  Single-Agent Cohorts (only applies to Dose Escalation): Advanced or metastatic disease
             that is either refractory to or intolerant of existing standard therapy or for which
             no effective standard therapy that confers clinical benefit is available

          -  Cohort B0: No prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor

          -  For participants undergoing 18F-fluoroestradiol-positron emission tomography (FES-PET)
             imaging additional restrictions on prior therapy include: ≥2 months must have elapsed
             from the use of tamoxifen; ≥6 months must have elapsed from the use of fulvestrant

          -  Postmenopausal status

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to
             (≤)1

          -  Resolution of all acute toxic effects of prior therapy or surgical procedures to
             baseline or Grade ≤1 (except alopecia or other toxicities not considered to be a
             safety risk for the patient)

          -  Life expectancy of ≥12 weeks

          -  Adequate organ function

        Inclusion Criteria for Dose Expansion:

        Same criteria as above for Dose Escalation, except for those that only apply to Dose
        Escalation, plus the following:

          -  Required paired pre- and on-treatment tumor biopsies for participants in Cohorts
             A1-A5, B1, and B2 with metastases that are safely accessible as determined by the
             investigator

          -  In South Korea: Must have received exactly 2 prior lines of treatment for advanced or
             metastatic breast cancer

          -  In the rest of the world: No more than 1 prior line of treatment for advanced or
             metastatic breast cancer (not applicable to Cohort X)

        Plus the following criteria:

          -  Cohorts B1 and B2: No prior treatment with CDK4/6 inhibitor

          -  Cohorts A1, A3, A5, B1, C1, and C2 only: Postmenopausal status

          -  Cohorts A2, A4, and B2 only: Participants not defined as postmenopausal; Age less than
             (<)56 years who have medical menopause on LHRH agonist (on stable dose ≥4 weeks)

          -  No prior treatment with an oral selective estrogen receptor degrader (SERD)

          -  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 40 days after the last dose
             of GDC-9545, and agreement to refrain from donating eggs during this same period

          -  Cohort X only: Participants enrolled on Studies GO29656 or GO29642 and received
             clinical benefit from GDC-0927 or GDC-0810

          -  Hematology, chemistry, and urinalysis collected 72 hours before Cycle 1, Day 1 deemed
             acceptable for dosing by the investigator

          -  No other endocrine therapy, targeted therapy, or chemotherapy after last dose of
             GDC-0927 or GDC-0810

        Exclusion Criteria for Dose Escalation:

          -  Known brain metastases that are untreated, symptomatic, or require therapy to control
             symptoms

          -  Current treatment with any systemic anti-cancer therapies for advanced disease (not
             applicable to Cohort X participants currently receiving GDC-0810 or GDC-0927)

          -  Concurrent treatment with warfarin or phenytoin

          -  Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for
             appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or
             Stage I uterine cancer

          -  Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major
             upper gastrointestinal (GI) surgery including gastric resection

          -  Known human immunodeficiency virus (HIV) infection

          -  Known clinically significant history of liver disease consistent with Child-Pugh Class
             B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C
             virus), current alcohol abuse, or cirrhosis

          -  Major surgery within 4 weeks prior to enrollment

          -  Radiation therapy within 2 weeks prior to enrollment

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the investigator, would make the patient
             inappropriate for entry into this study

          -  Inability or unwillingness to swallow tablets or capsules (only applies to Dose
             Escalation)

          -  Any serious medical condition or abnormality in clinical laboratory tests that, in the
             investigator's judgment, precludes the patient's safe participation in and completion
             of the study (only applies to Dose Escalation)

          -  History or presence of an abnormal electrocardiogram (ECG) that is clinically
             significant in the investigator's opinion, including complete left bundle branch
             block, second- or third-degree heart block, or evidence of prior myocardial infarction

          -  QT interval corrected using Fridericia's formula (QTcF) greater than (>)470
             milliseconds (ms) demonstrated by at least two ECGs >30 minutes apart

          -  History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such
             as structural heart disease coronary heart disease clinically significant electrolyte
             abnormalities or family history of sudden unexplained death or long QT syndrome

          -  Current treatment with medications that are well known to prolong the QT interval

        Exclusion Criteria for Dose Expansion:

        Same criteria as above for Dose Escalation, except for those that only apply to Dose
        Escalation, plus the following criteria:

          -  Pregnant, lactating, or breastfeeding

          -  Additional exclusion criteria for Cohort B (Phase 1b cohort): History of venous
             thromboembolic event requiring therapeutic anticoagulation

          -  Additional exclusion criteria for Cohorts C1 and C2 only: Current treatment with
             medications that are well known to decrease heart rate, including beta blockers
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Adverse Events by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0)
Time Frame:From Baseline until 28 days after the last dose of study treatment (up to 48 months)
Safety Issue:
Description:Laboratory parameters for hematology will be measured and compared with a standard reference range. Values outside of the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment, a medical intervention, or a change in concomitant therapy; or is clinically significant in the investigator's judgment.

Secondary Outcome Measures

Measure:Plasma Concentration of GDC-9545 Over Time
Time Frame:At predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation and A1-A5 only) or Cycle 1, Day 1 (B0, B1, and B2) to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion; Cycle 1, Days -7 or 8 (C1 only); Cycle 1, Day 8 (C2 only)
Safety Issue:
Description:
Measure:Plasma Concentration of Palbociclib Over Time
Time Frame:At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B0, B1, and B2 only); Cycle 1, Day 8 (C2 only)
Safety Issue:
Description:
Measure:Plasma Concentration of LHRH Over Time
Time Frame:At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B2 only)
Safety Issue:
Description:
Measure:Percentage of Participants with Objective Response
Time Frame:For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 48 months)
Safety Issue:
Description:Objective response is defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1).
Measure:Clinical Benefit Rate
Time Frame:For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 48 months)
Safety Issue:
Description:Clinical benefit rate is defined as the percentage of participants achieving either of the following: confirmed complete response or partial response (as determined by the investigator according to RECIST v1.1); or the first occurrence of progressive disease after 24 weeks of study treatment.
Measure:Duration of Response
Time Frame:For all cohorts, except for Cohort X: From the first occurrence of a documented objective response until first observation of disease progression or death from any cause on study, whichever occurs first (up to 48 months)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Genentech, Inc.

Last Updated

August 17, 2021