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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 patients with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 [HER2]-negative) breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

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-9545Dose Escalation: GDC-9545
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 patients 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, 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 at a dose lower than the MTD or MAD determined in single-agent dose escalation along with the label-recommended dose of Palbociclib.
  • GDC-9545
  • Palbociclib
Dose Expansion: Cohort A1: GDC-9545 Dose 1ExperimentalGDC-9545 will be administered as a single-agent at a dose lower than the MTD/MAD (Dose 1).
  • GDC-9545
Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRHExperimentalGDC-9545 will be administered at a dose lower than the MTD or MAD (Dose 1) along with an approved LHRH agonist.
  • GDC-9545
  • LHRH agonist
Dose Expansion: Cohort A3: GDC-9545 Dose 2ExperimentalGDC-9545 (Dose 2) will be administered as a single-agent at a dose at or below the MTD/MAD and above Dose 1.
  • GDC-9545
Dose Expansion: Cohort A4; GDC-9545 Dose 2 + LHRHExperimentalGDC-9545 will be administered at Dose 2 along with an LHRH agonist.
  • GDC-9545
  • LHRH agonist
Dose Expansion: Cohort B1: GDC-9545 + PalbociclibExperimentalGDC-9545 will be administered at a dose that is at or below MTD/MAD along with Palbociclib.
  • GDC-9545
  • Palbociclib
Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRHExperimentalGDC-9545 will be administered at or below MTD/MAD along with Palbociclib and an approved LHRH-agonist.
  • GDC-9545
  • Palbociclib
  • LHRH agonist

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

          -  ER-positive tumor

          -  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

          -  ≥ 2 weeks must have elapsed from the use of any other endocrine, targeted therapy or
             chemotherapy

          -  Cohort B0: No prior treatment with Cyclin-Dependent Kinase (CDK) 4/6 inhibitor

          -  For participants undergoing 18F-fluoroestradiol (FES) positron emission tomography
             (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 ≤ 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 as above, except:

          -  No more than one prior line of treatment for advanced or metastatic breast cancer

          -  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

        And plus:

          -  Cohort B1−2: No prior treatment with CDK4/6 inhibitor

          -  Cohorts A1, A3, and B1 only: Postmenopausal status

          -  Cohorts A2, A4, and B2 only: Participants not defined as post-menopausal

          -  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

        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

          -  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 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

        Exclusion Criteria for Dose Expansion:

        Same as above, plus:

          -  Pregnant, lactating, or breastfeeding

          -  Additional exclusion criteria for participants in Cohort B: History of venous
             thromboembolic event requiring therapeutic anticoagulation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Adverse Events
Time Frame:From baseline through end of study (up to 21 months)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Maximum Observed Plasma Concentration (Cmax) of GDC-9545 Administered as a Single Agent
Time Frame:At predefined intervals from Cycle 1, Day -7 through Cycle 4, Day 1 (4 months)
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of GDC-9545 Administered in Combination
Time Frame:At predefined intervals from Cycle 1, Day 1 through Cycle 4, Day 1 (4 months)
Safety Issue:
Description:
Measure:Objective Response
Time Frame:Baseline; Every 8 weeks from Cycle 1, Day 1 to end of study (up to 21 months)
Safety Issue:
Description:
Measure:Clinical Benefit Rate Assessed by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v 1.1)
Time Frame:From baseline to end of study (up to 21 months)
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:From the first occurrence of a documented objective response to the first observation of disease progression or death from any cause through the end of study (up to 21 months)
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of Palbociclib
Time Frame:At predefined intervals from Cycle 1, Day 1 through Cycle 4, Day 1 (4 months)
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of LHRH
Time Frame:At predefined intervals from Cycle 1, Day 1 through Cycle 4, Day 1 (4 months)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Genentech, Inc.

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