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 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GO296422014-004852-77
• Study Type: interventional
• Target: 152
• Locations: 4 countries
• Sites: 14

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

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (21)

• All Phases: Percentage of Participants With Adverse Events (AEs)

  up to 3 years

• Phase Ia: Maximum Plasma Concentration (Cmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites

  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

  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

  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

  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

Study Arms (15)

Phase Ia - Cohort 1

EXPERIMENTAL

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

Drug: GDC-0810

Phase Ia - Cohort 2

EXPERIMENTAL

200 mg GDC-0810 QD in fasting state.

Drug: GDC-0810

Phase Ia - Cohort 3

EXPERIMENTAL

400 mg GDC-0810 QD in fasting state.

Drug: GDC-0810

Phase Ia - Cohort 4

EXPERIMENTAL

600 mg GDC-0810 QD in fasting state.

Drug: GDC-0810

Phase Ia - Cohort 5

EXPERIMENTAL

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

Drug: GDC-0810

Phase Ia - Cohort 6

EXPERIMENTAL

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

Drug: GDC-0810

Phase Ia - Cohort 7

EXPERIMENTAL

800 mg GDC-0810 QD in fasting state.

Drug: GDC-0810

Phase Ia - Cohort 8

EXPERIMENTAL

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

Drug: GDC-0810

Phase Ia - Cohort 9

EXPERIMENTAL

400 mg GDC-0810 BID in fasting state.

Drug: GDC-0810

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).

Drug: GDC-0810

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.

Drug: GDC-0810

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).

Drug: GDC-0810

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.

Drug: GDC-0810

Phase Ib - Cohort C1

EXPERIMENTAL

400 mg GDC-0810 + 125 mg Palbociclib QD.

Drug: GDC-0810; Drug: Palbociclib

Phase Ib - Cohort D1

EXPERIMENTAL

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

Drug: GDC-0810; Drug: LHRH Agonist

Interventions

GDC-0810 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; Phase IIa - Cohort A2; Phase IIa - Cohort B1; Phase IIa - Cohort B2; Phase Ia - Cohort 1; Phase Ia - Cohort 2; Phase Ia - Cohort 3; Phase Ia - Cohort 4; Phase Ia - Cohort 5; Phase Ia - Cohort 6; Phase Ia - Cohort 7; Phase Ia - Cohort 8; Phase Ia - Cohort 9; Phase Ib - Cohort C1; Phase Ib - Cohort D1

LHRH Agonist 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.

Phase Ib - Cohort D1

Palbociclib 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 C1

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (14)

Ucsd Medical Center

San Diego, California, 92103-8465, United States

Location

Massachusetts General Hospital.

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Washington University

St Louis, Missouri, 63128, United States

Location

Mount SInai Medical Center

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

VU MEDISCH CENTRUM; Dept. of Medical Oncology

Amsterdam, 1081 HV, Netherlands

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica

Madrid, 28050, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

Related Publications (1)

• 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.

  PMID: 36401732 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid; Gonadotropin-Releasing Hormone; palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2013
• First Posted: April 4, 2013
• Study Start: December 29, 2014
• Primary Completion: March 13, 2020
• Study Completion: March 13, 2020
• Last Updated: June 18, 2021
• Results First Posted: June 18, 2021

Record last verified: 2021-05

Locations

US (8); NL (1); KR (2); ES (3)