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
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT03332797
- Lead Sponsor
- Genentech, Inc.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 181
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH LHRH Agonist 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. Dose Escalation: GDC-9545 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). Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH GDC-9545 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. Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH LHRH Agonist 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. Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH LHRH Agonist 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. Dose Expansion: Cohort A5: GDC-9545 Dose 3 GDC-9545 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). Dose Escalation: Cohort B0: GDC-9545 + Palbociclib GDC-9545 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. Dose Expansion: Cohort A1: GDC-9545 Dose 1 GDC-9545 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). Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH GDC-9545 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. Dose Expansion: Cohort A3: GDC-9545 Dose 2 GDC-9545 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). Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib GDC-9545 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. Dose Expansion: Cohort B1: GDC-9545 + Palbociclib GDC-9545 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. Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH GDC-9545 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. Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib GDC-9545 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. Dose Expansion: Cohort X: GDC-9545 Dose 3 GDC-9545 GDC-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. Dose Escalation: Cohort B0: GDC-9545 + Palbociclib 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. Dose Expansion: Cohort B1: GDC-9545 + Palbociclib 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. Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH Palbociclib 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. Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib 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. Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib 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.
- Primary Outcome Measures
Name Time Method 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) From Baseline until 28 days after the last dose of study treatment (up to 84 months) 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 Days -7 to 28 of Cycle 1 Change from Baseline in Diastolic Blood Pressure Over Time Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment Dose Escalation: Number of Participants with Dose-Limiting Toxicities When GDC-9545 is Administered as a Single Agent or in Combination with Palbociclib Days -7 to 28 of Cycle 1 Change from Baseline in ECG Results Over Time: QT Duration Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment Number of Participants with Clinical Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v4.0 Baseline, Cycle 1, and at each subsequent cycle (1 cycle is 28 days) or at every other cycle starting from Cycle 3 (Cohort X only), up to 28 days after the last dose of study treatment 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.
Change from Baseline in Pulse Rate Over Time Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment Change from Baseline in Systolic Blood Pressure Over Time Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment Change from Baseline in Body Temperature Over Time Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment Change from Baseline in Respiration Rate Over Time Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment Change from Baseline in Electrocardiogram (ECG) Results Over Time: Heart Rate Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment Change from Baseline in ECG Results Over Time: PR Duration Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment Change from Baseline in ECG Results Over Time: RR Duration Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment Change from Baseline in ECG Results Over Time: QRS Duration Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment Change from Baseline in ECG Results Over Time: QTcF Duration Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment Number of Participants with Clinical Laboratory Abnormalities in Urinalysis Tests by Highest Grade According to NCI-CTCAE v4.0 Baseline, Cycle 3, and at every other cycle (1 cycle is 28 days) up to 28 days after the last dose of study treatment Laboratory parameters for urinalysis 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.
Number of Participants with Clinical Laboratory Abnormalities in Blood Chemistry Tests by Highest Grade According to NCI-CTCAE v4.0 Baseline, Cycle 1, and at each subsequent cycle (1 cycle is 28 days) or at every other cycle starting from Cycle 3 (Cohort X only), up to 28 days after the last dose of study treatment Laboratory parameters for blood chemistry 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
Name Time Method Plasma Concentration of GDC-9545 Over Time 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) Plasma Concentration of Palbociclib Over Time 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) Percentage of Participants with Objective Response For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 84 months) 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).
Plasma Concentration of LHRH Over Time At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B2 only) Clinical Benefit Rate For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 84 months) 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.
Duration of Response 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 84 months)
Trial Locations
- Locations (23)
Hospital Quiron Barcelona
🇪🇸Barcelona, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸Madrid, Spain
Centro Oncologioco MD Anderson Internacional
🇪🇸Madrid, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
University of Colorado
🇺🇸Aurora, Colorado, United States
Massachusetts General Hospital.
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
St Vincent's Hospital Sydney
🇦🇺Darlinghurst, New South Wales, Australia
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
National Cancer Center
🇰🇷Gyeonggi-do, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
ICO L'Hospitalet
🇪🇸L'Hospitalet de Llobregat, Barcelona, Spain
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Universitario HM Sanchinarro
🇪🇸Madrid, Spain
Barts Health NHS Trust
🇬🇧London, United Kingdom
The Royal Marsden Hospital
🇬🇧Suttton, United Kingdom