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

NCT ID: NCT01823835

Last Updated: 2021-06-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 152 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-29
• Study Completion Date: 2020-03-13

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase Ia - Cohort 1

100 mg GDC-0810 once daily (QD) in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 2

200 mg GDC-0810 QD in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 3

400 mg GDC-0810 QD in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 4

600 mg GDC-0810 QD in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 5

600 mg GDC-0810 QD in non-fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 6

300 mg GDC-0810 twice daily (BID) in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 7

800 mg GDC-0810 QD in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 8

800 mg GDC-0810 QD in non-fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ia - Cohort 9

400 mg GDC-0810 BID in fasting state.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase IIa - Cohort A1

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).

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase IIa - Cohort A2

600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and confirmed ER-a (ESR1) mutation of the LBD.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase IIa - Cohort B1

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).

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase IIa - Cohort B2

600 mg GDC-0810 QD. Additionally, participants in this arm had prior treatment with fulvestrant and progressed following ≤1 prior therapy with an AI.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Phase Ib - Cohort C1

400 mg GDC-0810 + 125 mg Palbociclib QD.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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).

Palbociclib

Intervention Type: DRUG

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).

Phase Ib - Cohort D1

≤600 mg GDC-0810 QD + LHRH agonist once monthly.

Group Type: EXPERIMENTAL

GDC-0810

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Interventions

GDC-0810

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).

Intervention Type: DRUG

LHRH Agonist

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.

Intervention Type: DRUG

Palbociclib

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).

Intervention Type: DRUG

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

• 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

• 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

• Cohort C1 (palbociclib combination cohorts): history of venous thromboembolic event requiring therapeutic anticoagulation; vaginal bleeding within 2 months prior to enrollment

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

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

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica

Madrid, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Countries

United States; Netherlands; South Korea; Spain

References

Bardia A, Mayer I, Winer E, Linden HM, Ma CX, Parker BA, Bellet M, Arteaga CL, Cheeti S, Gates M, Chang CW, Fredrickson J, Spoerke JM, Moore HM, Giltnane J, Friedman LS, Chow Maneval E, Chan I, Jhaveri K. The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 -) advanced/metastatic breast cancer. Breast Cancer Res Treat. 2023 Jan;197(2):319-331. doi: 10.1007/s10549-022-06797-9. Epub 2022 Nov 19.

Reference Type: DERIVED

PMID: 36401732 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2014-004852-77

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GO29642

Identifier Type: -

Identifier Source: org_study_id