Clinical Trial - NCT03332797

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

Recruiting

Sponsor: Genentech, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03332797

Protocol Info

Short Description: 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
Long Description: 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
MGH Status: Open
Sponsor: Genentech
Disease Program: Breast

Next Steps


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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.
Condition Title Intervention Phase
Breast Cancer GDC-9545 Palbociclib LHRH Agonist Phase 1
Study Type Interventional
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

Primary Outcome Measures

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)] [Designated as safety issue: ]

Dose Escalation: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of GDC-9545 When Administered as a Single Agent or in Combination with Palbociclib [Time Frame: Days -7 to 28 of Cycle 1] [Designated as safety issue: ]

Dose Escalation: Number of Participants with Dose-Limiting Toxicities When GDC-9545 is Administered as a Single Agent or in Combination with Palbociclib [Time Frame: Days -7 to 28 of Cycle 1] [Designated as safety issue: ]

Change from Baseline in Systolic Blood Pressure Over Time [Time Frame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in Diastolic Blood Pressure Over Time [Time Frame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in Body Temperature Over Time [Time Frame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in Pulse Rate Over Time [Time Frame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in Respiration Rate Over Time [Time Frame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in Electrocardiogram (ECG) Results Over Time: Heart Rate [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in ECG Results Over Time: PR Duration [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in ECG Results Over Time: QRS Duration [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in ECG Results Over Time: QT Duration [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in ECG Results Over Time: QTcF Duration [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]

Change from Baseline in ECG Results Over Time: RR Duration [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]

Number of Participants with Grade ≥3 Adverse Events of Clinical Laboratory Test Abnormalities [Time Frame: Baseline and at predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation, A1-A5, and C2 only) or Cycle 1, Day 1 (B0, B1, and B2) and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment] [Designated as safety issue: ]


Secondary Outcome Measures

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

Percentage of Participants with Objective Response [Time Frame: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 48 months)] [Designated as safety issue: ]

Clinical Benefit Rate [Time Frame: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 48 months)] [Designated as safety issue: ]

Duration of Response [Time Frame: 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)] [Designated as safety issue: ]

Estimated Enrollment: 220
Study Start Date: November 2017
Estimated Study Completion Date: October 2021
Estimated Primary Completion Date: October 2021
Arms Assigned Interventions

Experimental:Dose Escalation: GDC-9545

During 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).
Drug:GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Experimental:Dose Escalation: Cohort B0: GDC-9545 + Palbociclib

GDC-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.
Drug:Palbociclib
Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Experimental:Dose Expansion: Cohort A1: GDC-9545 Dose 1

GDC-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).

Experimental:Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH

GDC-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.
Drug:LHRH Agonist
The LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. The investigator will choose the appropriate LHRH agonist approved for use in breast cancer.

Experimental:Dose Expansion: Cohort A3: GDC-9545 Dose 2

GDC-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).

Experimental:Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH

GDC-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.

Experimental:Dose Expansion: Cohort A5: GDC-9545 Dose 3

GDC-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).

Experimental:Dose Expansion: Cohort B1: GDC-9545 + Palbociclib

GDC-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.

Experimental:Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH

GDC-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.

Experimental:Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib

GDC-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.

Experimental:Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib

GDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2), in combination with the label-recommended dose of palbociclib.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: Female

Accepts Healthly Volunteers: No

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

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

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 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03332797

Locations

  • United States, Colorado
    • University of Colorado Aurora, Colorado, United States, 80045
  • United States, Massachusetts
    • Massachusetts General Hospital. Boston, Massachusetts, United States, 02114
    • Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02215
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215
  • United States, New York
    • Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065
  • United States, Tennessee
    • Vanderbilt University Medical Center; Vanderbilt University Nashville, Tennessee, United States, 37232
  • Australia, New South Wales
    • St Vincent's Hospital Sydney Darlinghurst, New South Wales, Australia, 2010
  • Australia, Victoria
    • Cabrini Hospital Malvern Malvern, Victoria, Australia, 3144
    • Peter Maccallum Cancer Centre Melbourne, Victoria, Australia, 3000
  • Korea, Republic of,
    • National Cancer Center; Medical Oncology Gyeonggi-do, , Korea, Republic of, 410-769
    • Seoul National University Hospital Seoul, , Korea, Republic of, 03080
    • Severance Hospital, Yonsei University Health System Seoul, , Korea, Republic of, 03722
    • Asan Medical Center - Oncology Seoul, , Korea, Republic of, 05505
    • Samsung Medical Center Seoul, , Korea, Republic of, 6351
  • Spain, Barcelona
    • ICO L'Hospitalet; Servicio de oncologia medica L Hospitalet De Llobregat, Barcelona, Spain, 08908
  • Spain, Guipuzcoa
    • Onkologikoa; Ensayos Clinicos Donostia, Guipuzcoa, Spain, 20014
  • Spain,
    • Hospital Quiron Barcelona; Servicio de Oncologia Barcelona, , Spain, 08024
    • Hospital Universitari Vall d'Hebron Barcelona, , Spain, 08035
    • MD Anderson Cancer Center Madrid - España; Servicio de Farmacia Madrid, , Spain, 28033
    • Hospital Universitario Ramón y Cajal Madrid, , Spain, 28034
    • Hospital General Universitario Gregorio Maranon Madrid, , Spain, 28040
    • Hospital Universitario HM Sanchinarro; South Texas Accelerated Research Therapeutics Madrid, , Spain, 28050
    • Hospital Clinico Universitario de Valencia Valencia, , Spain, 46010
  • United Kingdom,
    • Barts Health NHS Trust London, , United Kingdom, E1 2ES
    • The Royal Marsden NHS Foundation Trust; Oncology London, , United Kingdom, SW3 6JJ
    • The Royal Marsden Hospital Sutton, , United Kingdom, SM2 5PT

Sponsors and Collaborators

Genentech, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03332797
Other Study ID Numbers: 2017-002083-41
Study First Received:
Last Updated:
Health Authority:

Additional relevant MeSH terms:

Breast Neoplasms

Estrogens

Palbociclib

Prolactin Release-Inhibiting Factors

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019