Description:
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.
Title
- Brief Title: 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
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
GO29642
- SECONDARY ID:
2014-004852-77
- NCT ID:
NCT01823835
Conditions
Interventions
Drug | Synonyms | Arms |
---|
GDC-0810 | | Phase IIa - Cohort A1 |
LHRH Agonist | | Phase Ib - Cohort D1 |
Palbociclib | | Phase Ib - Cohort C1 |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Phase Ia - Cohort 1 | Experimental | 100 mg GDC-0810 once daily (QD) in fasting state. | |
Phase Ia - Cohort 2 | Experimental | 200 mg GDC-0810 QD in fasting state. | |
Phase Ia - Cohort 3 | Experimental | 400 mg GDC-0810 QD in fasting state. | |
Phase Ia - Cohort 4 | Experimental | 600 mg GDC-0810 QD in fasting state. | |
Phase Ia - Cohort 5 | Experimental | 600 mg GDC-0810 QD in non-fasting state. | |
Phase Ia - Cohort 6 | Experimental | 300 mg GDC-0810 twice daily (BID) in fasting state. | |
Phase Ia - Cohort 7 | Experimental | 800 mg GDC-0810 QD in fasting state. | |
Phase Ia - Cohort 8 | Experimental | 800 mg GDC-0810 QD in non-fasting state. | |
Phase Ia - Cohort 9 | Experimental | 400 mg GDC-0810 BID in fasting state. | |
Phase IIa - Cohort A1 | Experimental | 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 | Experimental | 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 IIa - Cohort B1 | Experimental | 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 | Experimental | 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 | Experimental | 400 mg GDC-0810 + 125 mg Palbociclib QD. | |
Phase Ib - Cohort D1 | Experimental | ≤600 mg GDC-0810 QD + LHRH agonist once monthly. | |
Eligibility Criteria
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Female |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Phase Ia: Maximum Tolerated Dose of GDC-0810 When Used as a Single Agent |
Time Frame: | Day -7 through the first cycle (28 days) of treatment (35 days total) |
Safety Issue: | |
Description: | 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 |
Secondary Outcome Measures
Measure: | All Phases: Percentage of Participants With Adverse Events (AEs) |
Time Frame: | up to 3 years |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ia: Maximum Plasma Concentration (Cmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ia: Time to Maximum Concentration (Tmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ia: Area Under the Concentration-time Curves at 6 Hours (AUC0-6) of GDC-0810 Single Agent and Its Glucuronide Metabolites |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ia: Area Under the Concentration-time Curves at 24 Hours (AUC0-24) of GDC-0810 Single Agent and Its Glucuronide Metabolites |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf) |
Time Frame: | Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ia: Plasma Half-life (t1/2) of GDC-0810 Single Agent |
Time Frame: | Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose |
Safety Issue: | |
Description: | Half-life (t1/2) was calculated after single dose administration and not at steady state. |
Measure: | Phase Ia: Apparent Clearance (Cl/F) |
Time Frame: | Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose |
Safety Issue: | |
Description: | Apparent Clearance (CL/F) was estimated using PK samples collected following administration of a single dose (on Day -7) of GDC-0810 |
Measure: | Phase IIa: Effect of GDC-0810 Single Agent on Ventricular Repolarization as Measured by Corrected QT Intervals (QTc) Using Fridericia's Formula |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ib: Cmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist |
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 |
Safety Issue: | |
Description: | Cmax has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: Tmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist |
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 |
Safety Issue: | |
Description: | Tmax has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: AUC0-6 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist |
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 |
Safety Issue: | |
Description: | AUC0-6 has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: t/2 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ib: Cmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist |
Time Frame: | Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8 |
Safety Issue: | |
Description: | Cmax has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: Tmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist |
Time Frame: | Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8 |
Safety Issue: | |
Description: | Tmax has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: AUC0-6 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist |
Time Frame: | Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8 |
Safety Issue: | |
Description: | AUC0-6 has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: t/2 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist |
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 |
Safety Issue: | |
Description: | 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. |
Measure: | Phase Ib: Cmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib |
Time Frame: | Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1 |
Safety Issue: | |
Description: | Cmax has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: Tmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib |
Time Frame: | Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1 |
Safety Issue: | |
Description: | Tmax has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: AUC0-6 of LHRH Agonist in Combination With GDC-0810 and/or an Palbociclib |
Time Frame: | Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1 |
Safety Issue: | |
Description: | AUC0-6 has been calculated using PK samples collected after GDC-0810 administration. |
Measure: | Phase Ib: t/2 of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib |
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 |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Genentech, Inc. |
Last Updated
June 18, 2021