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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
152
GDC-0810 administered orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, GDC-0810 drug supply exhausted, or study termination (up to 3 years).
LHRH agonist administered once monthly until disease progression, unacceptable toxicity, withdrawal of consent, GDC-0810 drug supply exhausted, or study termination (up to 3 years). Choice of LHRH agonist will be an institutional choice approved for use in breast cancer.
Palbociclib administered orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, GDC-0810 drug supply exhausted, or study termination (up to 3 years).
Ucsd Medical Center
San Diego, California, United States
Massachusetts General Hospital.
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Washington University
St Louis, Missouri, United States
Mount SInai Medical Center
New York, New York, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Seattle Cancer Care Alliance
Seattle, Washington, United States
VU MEDISCH CENTRUM; Dept. of Medical Oncology
Amsterdam, Netherlands
Seoul National University Hospital
Seoul, South Korea
...and 4 more locations
Phase Ia: Maximum Tolerated Dose of GDC-0810 When Used as a Single Agent
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
Time frame: Day -7 through the first cycle (28 days) of treatment (35 days total)
Phase Ia: RP2D of GDC-0810 When Used as a Single Agent
The recommended Phase II dose (RP2D) was based on the overall safety/tolerability and pharmacokinetic profile of GDC-0810.
Time frame: Day -7 through the first cycle (28 days) of treatment (35 days total)
Phase IIa: Percentage of Participants With Confirmed Objective Tumor Response of GDC-0810 According to RECIST v1.1
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.
Time frame: Screening and every 8 weeks from Cycle 1 Day 1 until Cycle 12, thereafter every 3 months until disease progression (up to 3 years)
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)
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.
Time frame: Screening and every 8 weeks from Cycle 1 Day 1 until Cycle 12, thereafter every 3 months until disease progression (up to 3 years)
Phase Ib: RP2D of GDC-0810 When Used in Combination With Palbociclib and/or LHRH
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.
Time frame: first cycle (Days 1 to 28 of a 28-day schedule)
All Phases: Percentage of Participants With Adverse Events (AEs)
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.
Time frame: up to 3 years
Phase Ia: Maximum Plasma Concentration (Cmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites
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.
Time frame: 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
Phase Ia: Time to Maximum Concentration (Tmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites
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.
Time frame: 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
Phase Ia: Area Under the Concentration-time Curves at 6 Hours (AUC0-6) of GDC-0810 Single Agent and Its Glucuronide Metabolites
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.
Time frame: 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
Phase Ia: Area Under the Concentration-time Curves at 24 Hours (AUC0-24) of GDC-0810 Single Agent and Its Glucuronide Metabolites
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.
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Time frame: 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 Curve From Time 0 to Infinity (AUC0-Inf)
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.
Time frame: Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours postdose
Phase Ia: Plasma Half-life (t1/2) of GDC-0810 Single Agent
Half-life (t1/2) was calculated after single dose administration and not at steady state.
Time frame: Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose
Phase Ia: Apparent Clearance (Cl/F)
Apparent Clearance (CL/F) was estimated using PK samples collected following administration of a single dose (on Day -7) of GDC-0810
Time frame: Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose
Phase IIa: Effect of GDC-0810 Single Agent on Ventricular Repolarization as Measured by Corrected QT Intervals (QTc) Using Fridericia's Formula
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.
Time frame: 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
Phase Ib: Cmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
Cmax has been calculated using PK samples collected after GDC-0810 administration.
Time frame: 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
Phase Ib: Tmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
Tmax has been calculated using PK samples collected after GDC-0810 administration.
Time frame: 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
Phase Ib: AUC0-6 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
AUC0-6 has been calculated using PK samples collected after GDC-0810 administration.
Time frame: 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
Phase Ib: t/2 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
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.
Time frame: 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
Phase Ib: Cmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
Cmax has been calculated using PK samples collected after GDC-0810 administration.
Time frame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
Phase Ib: Tmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
Tmax has been calculated using PK samples collected after GDC-0810 administration.
Time frame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
Phase Ib: AUC0-6 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
AUC0-6 has been calculated using PK samples collected after GDC-0810 administration.
Time frame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
Phase Ib: t/2 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
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.
Time frame: Cohort C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
Phase Ib: Cmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib
Cmax has been calculated using PK samples collected after GDC-0810 administration.
Time frame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
Phase Ib: Tmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib
Tmax has been calculated using PK samples collected after GDC-0810 administration.
Time frame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
Phase Ib: AUC0-6 of LHRH Agonist in Combination With GDC-0810 and/or an Palbociclib
AUC0-6 has been calculated using PK samples collected after GDC-0810 administration.
Time frame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
Phase Ib: t/2 of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib
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.
Time frame: Cohort D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1