A Study of GDC-0810 Single Agent or in Combination With Palbociclib and/or a Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer

Phase 1

Terminated

Conditions: Breast Cancer

Interventions: Drug: GDC-0810
Drug: LHRH Agonist
Drug: Palbociclib

Registration Number: NCT01823835

Lead Sponsor: Genentech, Inc.

Brief Summary: This study is a multi-institution, Phase Ia/Ib/IIa open-label, dose-finding, safety, pharmacokinetics (PK), and proof-of-concept study of GDC-0810 as a single agent and in combination with palbociclib and/or LHRH agonist. The study is divided into 3 phases: Phase Ia, Phase Ib, and Phase IIa. During Phase Ia (dose escalation phase), GDC-0810 single agent will be administered orally on a continuous daily dosing regimen with a Day -7 lead-in period for single dose PK evaluation prior to the start of daily treatment. The incidence of dose-limiting toxicities (DLTs) will be evaluated from Day -7 through the first cycle (28 days) of treatment (35 days total). Depending on safety and tolerability, participants will be assigned sequentially to escalating doses of GDC-0810 using standard 3 + 3 design. During Phase Ib (dose escalation and expansion phase), participants will receive GDC-0810 with palbociclib and/or LHRH agonist to determine the recommended Phase II dose (RP2D) and assess the safety and tolerability of concomitant administration. During Phase IIa (dose expansion phase), participants previously treated with an aromatase inhibitor (AI) will be treated at the RP2D to further characterize the safety, PK, pharmacodynamics, and anti-tumor activity of GDC-0810.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 152

Inclusion Criteria

Phase 1a portion

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 metastatic disease, both progressing after at least 6 months of hormonal therapy for estrogen receptor (ER) positive breast cancer
ER-positive, human epidermal growth factor 2 (HER2) negative
At least 2 months must have elapsed from the use of tamoxifen
At least 6 months must have elapsed from the use of fulvestrant
At least 2 weeks must have elapsed from the use of any other anticancer hormonal therapy
At least 3 weeks must have elapsed from the use of any chemotherapy
Postmenopausal status
Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
Adequate organ function

Phase Ib portion

All above inclusion criteria, except:
Postmenopausal status, pre- and peri-menopausal participants will also be included
ECOG performance status less than 2
At least 2 months must have elapsed from the use of tamoxifen not applicable
At least 6 months must have elapsed from the use of fulvestrant not applicable

and plus:

Documented sensitivity to prior hormonal therapy
Cohort C1 (palbociclib combination cohorts): no prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitor

Phase IIa portion

All above inclusion criteria for Phase Ia, except:
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
At least 6 months must have elapsed from the use of fulvestrant not applicable

and plus:

Cohort A only: confirmed estrogen receptor alpha (ESR1) mutation and presence of measurable disease as per RECIST v1.1 or evaluable bone disease
Cohort A1 only: no prior fulvestrant allowed; at least 2 months must have elapsed from the use of tamoxifen
Cohort A2 only: prior fulvestrant allowed
Cohort B only: disease progression following no more than 1 prior treatment with an aromatase inhibitor in the advanced/metastatic setting
Cohort B1 only: no prior fulvestrant allowed
Cohort B2 only: prior fulvestrant allowed

Exclusion Criteria

Phase 1a portion

Untreated or symptomatic central nervous system (CNS) metastases
Endometrial disorders
More than 2 prior chemotherapy in the advanced/metastatic setting (prior adjuvant chemotherapy is allowed so long as it occurred greater than or equal to 12 months prior to enrollment)
Current treatment with any systemic anticancer therapies for advanced disease
Any significant cardiac dysfunction within 12 months prior to enrollment
Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or upper gastrointestinal surgery including gastric resection
Known human immunodeficiency virus (HIV) infection
Known clinically significant history of liver disease
Major surgery within 4 weeks prior to enrollment
Radiation therapy within 2 weeks prior to enrollment

Phase Ib portion - all above exclusion criteria, plus:

Cohort C1 (palbociclib combination cohorts): history of venous thromboembolic event requiring therapeutic anticoagulation; vaginal bleeding within 2 months prior to enrollment

Phase IIa portion - all above exclusion criteria, plus:

Cohort A1, A2, and Cohort B2 only: more than 1 prior chemotherapy in the advanced/metastatic setting
Cohort B1 only: prior chemotherapy in the advanced/metastatic setting

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase Ib - Cohort D1	LHRH Agonist	≤600 mg GDC-0810 QD + LHRH agonist once monthly.
Phase Ia - Cohort 3	GDC-0810	400 mg GDC-0810 QD in fasting state.
Phase Ia - Cohort 1	GDC-0810	100 mg GDC-0810 once daily (QD) in fasting state.
Phase Ia - Cohort 7	GDC-0810	800 mg GDC-0810 QD in fasting state.
Phase Ia - Cohort 6	GDC-0810	300 mg GDC-0810 twice daily (BID) in fasting state.
Phase Ia - Cohort 9	GDC-0810	400 mg GDC-0810 BID in fasting state.
Phase Ib - Cohort D1	GDC-0810	≤600 mg GDC-0810 QD + LHRH agonist once monthly.
Phase IIa - Cohort A1	GDC-0810	600 mg GDC-0810 QD. Additionally, participants in this arm did not receive any prior treatment with fulvestrant and had confirmed ER-a (ESR1) mutation of the ligand binding domain (LBD).
Phase IIa - Cohort A2	GDC-0810	600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and confirmed ER-a (ESR1) mutation of the LBD.
Phase Ib - Cohort C1	Palbociclib	400 mg GDC-0810 + 125 mg Palbociclib QD.
Phase Ia - Cohort 2	GDC-0810	200 mg GDC-0810 QD in fasting state.
Phase Ia - Cohort 4	GDC-0810	600 mg GDC-0810 QD in fasting state.
Phase Ia - Cohort 5	GDC-0810	600 mg GDC-0810 QD in non-fasting state.
Phase Ia - Cohort 8	GDC-0810	800 mg GDC-0810 QD in non-fasting state.
Phase IIa - Cohort B1	GDC-0810	600 mg GDC-0810 QD. Additionally, participants in this arm did not receive any prior treatment with fulvestrant and had progressed following ≤1 prior therapy with an aromatase inhibitor (AI).
Phase IIa - Cohort B2	GDC-0810	600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and progressed following ≤1 prior therapy with an AI.
Phase Ib - Cohort C1	GDC-0810	400 mg GDC-0810 + 125 mg Palbociclib QD.

Primary Outcome Measures

Name	Time	Method
Phase Ia: Maximum Tolerated Dose of GDC-0810 When Used as a Single Agent	Day -7 through the first cycle (28 days) of treatment (35 days total)	Maximum Tolerated Dose (MTD) is determined based on the number of Dose Limiting Toxicities (DLTs) experienced by the participants. DLTs were defined as any of the following adverse events (AEs) that are deemed by the investigator or the Sponsor to be related to study drug (toxicities will be attributed to single agent GDC-0810 unless they are clearly related to disease progression or can clearly be attributed to a cause other than GDC-0810 administration): * Any grade ≥ 3 non-hematologic toxicity (excluding alopecia) * Any grade ≥ 3 hematologic toxicity of \> 7 days' duration * Any grade toxicity that leads to study drug interruption of \> 7 days' duration
Phase Ia: RP2D of GDC-0810 When Used as a Single Agent	Day -7 through the first cycle (28 days) of treatment (35 days total)	The recommended Phase II dose (RP2D) was based on the overall safety/tolerability and pharmacokinetic profile of GDC-0810.
Phase IIa: Percentage of Participants With Clinical Benefit Response of GDC-0810 According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	Screening and every 8 weeks from Cycle 1 Day 1 until Cycle 12, thereafter every 3 months until disease progression (up to 3 years)	Clinical Benefit Response (CBR) is defined as the percentage of participants achieving confirmed RECIST v1.1 defined CR, PR, and/or stable disease. CR was the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
Phase IIa: Percentage of Participants With Confirmed Objective Tumor Response of GDC-0810 According to RECIST v1.1	Screening and every 8 weeks from Cycle 1 Day 1 until Cycle 12, thereafter every 3 months until disease progression (up to 3 years)	Objective response (OR) is defined as a complete response (CR) or partial response (PR) as determined by investigator assessment according to RECIST v1.1. OR was based on criteria related to changes in size of target lesions. CR was the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Phase Ib: RP2D of GDC-0810 When Used in Combination With Palbociclib and/or LHRH	first cycle (Days 1 to 28 of a 28-day schedule)	The RP2D of GDC-0810 When Used in Combination With Palbociclib and/or LHRH RP2D was not determined since the development of the GDC-0810 was discontinued before enrolling Cohort C2. The RP2D would have been based on the overall safety and PK/PD profile of GDC-0810 and palbociclib, and not necessarily the MTD.

Secondary Outcome Measures

Name	Time	Method
Phase Ia: Maximum Plasma Concentration (Cmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites	Single Dose: Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose; Multiple Doses: Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, hours postdose	Maximum Plasma Concentration (Cmax) has been calculated using PK samples collected after administration of a single dose (on Day -7) and also following once-daily multiple doses (at steady state on Day 29) of GDC-0810.
Phase Ia: Apparent Clearance (Cl/F)	Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose	Apparent Clearance (CL/F) was estimated using PK samples collected following administration of a single dose (on Day -7) of GDC-0810
All Phases: Percentage of Participants With Adverse Events (AEs)	up to 3 years	An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
Phase Ia: Area Under the Concentration-time Curves at 6 Hours (AUC0-6) of GDC-0810 Single Agent and Its Glucuronide Metabolites	Single Dose: Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6 hours postdose; Multiple Doses: Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6 hours postdose	Area under the concentration-time curves from time 0 to 6 hours (AUC0-6) has been calculated using PK samples collected after administration of a single dose (on Day -7) and also following once-daily multiple doses (at steady state on Day 29) of GDC-0810.
Phase IIa: Effect of GDC-0810 Single Agent on Ventricular Repolarization as Measured by Corrected QT Intervals (QTc) Using Fridericia's Formula	Screening; on Cycle 2 Day 1 predose and at 1, 2, 3, 4, and 6 hours postdose; Cycle 3 Day 1 predose, and at 1, 3, and 6 hours post dose	The corrected QT interval (QTc) was calculated using Fridericia's formula from electrocardiogram (ECG) data. Changes in ECG intervals from baseline were calculated. Triplicate ECG measurements were collected throughout the study. The averaged triplicate ECG measurements were used for analysis.
Phase Ib: Cmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib	Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	Cmax has been calculated using PK samples collected after GDC-0810 administration.
Phase Ia: Time to Maximum Concentration (Tmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites	Single Dose: Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose; Multiple Doses: Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, hours postdose	Time to Maximum Concentration (Tmax) has been calculated using PK samples collected after administration of a single dose (on Day -7) and also following once-daily multiple doses (at steady state on Day 29) of GDC-0810.
Phase Ia: Area Under the Concentration-time Curves at 24 Hours (AUC0-24) of GDC-0810 Single Agent and Its Glucuronide Metabolites	Single Dose: Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours postdose; Multiple Doses: Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours postdose	Area under the concentration-time curves from time 0 to 24 hours (AUC0-24) has been calculated using PK samples collected after administration of a single dose (on Day -7) and also following once-daily multiple doses (at steady state on Day 29) of GDC-0810.
Phase Ib: Tmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist	C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8; D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	Tmax has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: AUC0-6 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist	C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8; D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	AUC0-6 has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: t/2 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist	C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8; D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	Half-life (t1/2) can be estimated only when the PK sample collection following a dose is long enough to characterize the elimination phase. The PK samples in these cohorts were only collected up to 6 hours following the dose, hence, t1/2 could not be estimated.
Phase Ib: Tmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib	Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	Tmax has been calculated using PK samples collected after GDC-0810 administration.
Phase Ia: Plasma Half-life (t1/2) of GDC-0810 Single Agent	Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose	Half-life (t1/2) was calculated after single dose administration and not at steady state.
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf)	Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours postdose	Area under the concentration-time curve from time 0-infinity (AUC0-inf) has been calculated using PK samples collected after administration of a single dose (on Day -7) of GDC-0810.
Phase Ib: Cmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist	C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8; D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	Cmax has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: Tmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist	Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8	Tmax has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: Cmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist	Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8	Cmax has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: AUC0-6 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist	Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8	AUC0-6 has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: t/2 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist	Cohort C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8	Half-life (t1/2) can be estimated only when the PK sample collection following a dose is long enough to characterize the elimination phase. The PK samples in these cohorts were only collected up to 6 hours following the dose, hence, t1/2 could not be estimated.
Phase Ib: AUC0-6 of LHRH Agonist in Combination With GDC-0810 and/or an Palbociclib	Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	AUC0-6 has been calculated using PK samples collected after GDC-0810 administration.
Phase Ib: t/2 of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib	Cohort D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1	Half-life (t1/2) can be estimated only when the PK sample collection following a dose is long enough to characterize the elimination phase. The PK samples in these cohorts were only collected up to 6 hours following the dose, hence, t1/2 could not be estimated.

Trial Locations

Locations (14): VU MEDISCH CENTRUM; Dept. of Medical Oncology
🇳🇱
Amsterdam, Netherlands
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Washington University
🇺🇸
Saint Louis, Missouri, United States
Hospital Clinico Universitario de Valencia
🇪🇸
Valencia, Spain
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
Seoul National University Hospital
🇰🇷
Seoul, Korea, Republic of
Massachusetts General Hospital.
🇺🇸
Boston, Massachusetts, United States
Severance Hospital, Yonsei University Health System
🇰🇷
Seoul, Korea, Republic of
Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
🇪🇸
Madrid, Spain
Ucsd Medical Center
🇺🇸
San Diego, California, United States
Mount SInai Medical Center
🇺🇸
New York, New York, United States
Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States