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

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label, Phase Ia/Ib/IIa Study of GDC-0810 Single Agent or in Combination With Palbociclib and/or an LHRH Agonist in Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: GDC-0810
* Drug: LHRH Agonist
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ia - Cohort 1<br>100 mg GDC-0810 once daily (QD) in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 2<br>200 mg GDC-0810 QD in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 3<br>400 mg GDC-0810 QD in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 4<br>600 mg GDC-0810 QD in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 5<br>600 mg GDC-0810 QD in non-fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 6<br>300 mg GDC-0810 twice daily (BID) in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 7<br>800 mg GDC-0810 QD in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 8<br>800 mg GDC-0810 QD in non-fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ia - Cohort 9<br>400 mg GDC-0810 BID in fasting state. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase IIa - Cohort A1<br>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). | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase IIa - Cohort A2<br>600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and confirmed ER-a (ESR1) mutation of the LBD. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase IIa - Cohort B1<br>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). | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase IIa - Cohort B2<br>600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and progressed following ≤1 prior therapy with an AI. | Drug: GDC-0810<br>* 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).<br>|
| Experimental: Phase Ib - Cohort C1<br>400 mg GDC-0810 + 125 mg Palbociclib QD. | Drug: GDC-0810<br>* 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).<br>Drug: Palbociclib<br>* 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).<br>|
| Experimental: Phase Ib - Cohort D1<br>≤600 mg GDC-0810 QD + LHRH agonist once monthly. | Drug: GDC-0810<br>* 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).<br>Drug: LHRH Agonist<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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. | 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. | 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. | first cycle (Days 1 to 28 of a 28-day schedule) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Cohort D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1 |