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

• ClinicalTrials.gov Identifier: NCT01823835
• Recruitment Status: Terminated
• First Posted: April 4, 2013
• Last Update Posted: March 23, 2020
• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: GDC-0810; Drug: LHRH Agonist; Drug: Palbociclib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 152 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 29, 2014
• Actual Primary Completion Date: March 13, 2020
• Actual Study Completion Date: March 13, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: GDC-0810 + Palbociclib and/or an LHRH Agonist; The 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).	Drug: LHRH Agonist; LHRH agonist will be administered once monthly until disease progression, unacceptable toxicity, or withdrawal of consent (up to 3 years). Choice of LHRH agonist will be an institutional choice approved for use in breast cancer.; Drug: Palbociclib; Palbociclib will be administered orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent (up to 3 years).
Experimental: GDC-0810 Single Agent; During 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).	Drug: GDC-0810; GDC-0810 will be administered orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent (up to 3 years).

Outcome Measures

Primary Outcome Measures :

1. 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) ]
2. Phase IIa: Percentage of Participants With Confirmed Objective Tumor Response of GDC-0810 According to RECIST v1.1 [ 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) ]
3. Phase Ia: Maximum Tolerated Dose (MTD) of GDC-0810 When Used as a Single Agent [ Time Frame: Day -7 through the first cycle (28 days) of treatment (35 days total) ]
4. Phase Ia: RP2D of GDC-0810 When Used as a Single Agent [ Time Frame: Day -7 through the first cycle (28 days) of treatment (35 days total) ]
5. 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) [ 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) ]

Secondary Outcome Measures :

1. 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 ]
2. 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) ]
3. 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) ]
4. 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) ]
5. 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) ]
6. 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 ]
7. 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 ]
8. 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 ]
9. 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 ]
10. 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 ]
11. 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 ]
12. 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 ]
13. 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 ]
14. All Phases: Number of Participants With Adverse Events [ Time Frame: up to 3 years ]
15. 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) ]
16. 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) ]
17. 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) ]
18. 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) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Ucsd Medical Center

San Diego, California, United States, 92103-8465

United States, Massachusetts

Massachusetts General Hospital.

Boston, Massachusetts, United States, 02114

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63128

United States, New York

Mount SInai Medical Center

New York, New York, United States, 10029

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Korea, Republic of

Seoul National University Hospital

Seoul, Korea, Republic of, 03080

Severance Hospital, Yonsei University Health System

Seoul, Korea, Republic of, 03722

Netherlands

VU MEDISCH CENTRUM; Dept. of Medical Oncology

Amsterdam, Netherlands, 1081 HV

Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain, 08035

Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica

Madrid, Spain, 28050

Hospital Clinico Universitario de Valencia

Valencia, Spain, 46010

Sponsors and Collaborators

Genentech, Inc.

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01823835
• Other Study ID Numbers: GO29642; 2014-004852-77 ( EudraCT Number )
• First Posted: April 4, 2013
• Last Update Posted: March 23, 2020
• Last Verified: March 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Palbociclib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action