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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

NCT01823835

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

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

  • Breast Cancer

Interventions

DrugSynonymsArms
GDC-0810GDC-0810 Single Agent
LHRH AgonistGDC-0810 + Palbociclib and/or an LHRH Agonist
PalbociclibGDC-0810 + Palbociclib and/or an LHRH Agonist

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

NameTypeDescriptionInterventions
GDC-0810 + Palbociclib and/or an LHRH AgonistExperimentalThe starting dose for Cohort C1 dose escalation of GDC-0810 will be 400 mg per day on Days 1 to 28 of a 28-day schedule, taken together with 125 mg palbociclib administered on Days 1 to 21 of a 28-day schedule. Dose escalation will be performed in Cohort C1. In Cohort D1, GDC-0810 600 mg will be administered orally on Days 1 to 28 of a 28-day schedule and an LHRH agonist administered monthly. Treatments will continue until disease progression, unacceptable toxicity, or withdrawal of consent (up to 3 years).
  • LHRH Agonist
  • Palbociclib
GDC-0810 Single AgentExperimentalDuring dose escalation (Phase I), GDC-0810 will be administered orally once daily in ascending-dose levels with a starting dose of 100 milligrams (mg) once daily. During dose expansion (Phase IIa), GDC-0810 will be administered at the MTD or RP2D define in dose escalation part of the study. Treatments will continue until disease progression, unacceptable toxicity, or withdrawal of consent (up to 3 years).
  • GDC-0810

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 Ib: RP2D of GDC-0810 When Used in Combination With Palbociclib and/or LHRH
Time Frame:first cycle (Days 1 to 28 of a 28-day schedule)
Safety Issue:
Description:

Secondary Outcome Measures

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:
Measure:Phase Ib: Cmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
Time Frame:Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 (Cohorts C1 and D1), Cycle 1 Day 8 (Cohort C1), and Cycle 2 Day 1 (Cohort D1)
Safety Issue:
Description:
Measure:Phase Ib: Tmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
Time Frame:Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 (Cohorts C1 and D1), Cycle 1 Day 8 (Cohort C1), and Cycle 2 Day 1 (Cohort D1)
Safety Issue:
Description:
Measure:Phase Ib: AUC of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
Time Frame:Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 (Cohorts C1 and D1), Cycle 1 Day 8 (Cohort C1), and Cycle 2 Day 1 (Cohort D1)
Safety Issue:
Description:
Measure:Phase Ib: t/2 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
Time Frame:Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 (Cohorts C1 and D1), Cycle 1 Day 8 (Cohort C1), and Cycle 2 Day 1 (Cohort D1)
Safety Issue:
Description:
Measure:Phase Ib: Cmax 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:
Measure:Phase Ib: Tmax 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:
Measure:Phase Ib: AUC 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:
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:
Measure:Phase Ib: Cmax 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:
Measure:Phase Ib: Tmax 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:
Measure:Phase Ib: AUC of LHRH Agonist in Combination With GDC-0810 and/or an 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:
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:
Measure:All Phases: Number of Participants With Adverse Events
Time Frame:up to 3 years
Safety Issue:
Description:
Measure:Phase Ia: Maximum Plasma Concentration (Cmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites
Time Frame:Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 (Day -6), and 48 (Day -5) hours postdose; Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose (Cycle 2 Day 2, prior to the next dose)
Safety Issue:
Description:
Measure:Phase Ia: Time to Maximum Concentration (Tmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites
Time Frame:Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 (Day -6), and 48 (Day -5) hours postdose; Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose (Cycle 2 Day 2, prior to the next dose)
Safety Issue:
Description:
Measure:Phase Ia: Area Under the Concentration-time Curve (AUC) of GDC-0810 Single Agent and Its Glucuronide Metabolites
Time Frame:Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 (Day -6), and 48 (Day -5) hours postdose; Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose (Cycle 2 Day 2, prior to the next dose)
Safety Issue:
Description:
Measure:Phase Ia: Plasma Half-life (t1/2) of GDC-0810 Single Agent and Its Glucuronide Metabolites
Time Frame:Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 (Day -6), and 48 (Day -5) hours postdose; Day 29 (Cycle 2 Day 1) at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose (Cycle 2 Day 2, prior to the next dose)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Genentech, Inc.

Last Updated

November 15, 2017