Clinical trial NCT01823835: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2013-04-04
Enrollment: 152
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Phase Ia: Maximum Tolerated Dose of GDC-0810 When Used as a Single Agent
timeFrame: Day -7 through the first cycle (28 days) of treatment (35 days total)
measure: Phase Ia: RP2D of GDC-0810 When Used as a Single Agent
timeFrame: Day -7 through the first cycle (28 days) of treatment (35 days total)
measure: Phase IIa: Percentage of Participants With Confirmed Objective Tumor Response of GDC-0810 According to RECIST v1.1
timeFrame: Screening and every 8 weeks from Cycle 1 Day 1 until Cycle 12, thereafter every 3 months until disease progression (up to 3 years)
measure: 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)
timeFrame: Screening and every 8 weeks from Cycle 1 Day 1 until Cycle 12, thereafter every 3 months until disease progression (up to 3 years)
measure: Phase Ib: RP2D of GDC-0810 When Used in Combination With Palbociclib and/or LHRH
timeFrame: first cycle (Days 1 to 28 of a 28-day schedule)
Secondary outcomes:
measure: All Phases: Percentage of Participants With Adverse Events (AEs)
timeFrame: up to 3 years
measure: Phase Ia: Maximum Plasma Concentration (Cmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites
timeFrame: 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
measure: Phase Ia: Time to Maximum Concentration (Tmax) of GDC-0810 Single Agent and Its Glucuronide Metabolites
timeFrame: 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
measure: Phase Ia: Area Under the Concentration-time Curves at 6 Hours (AUC0-6) of GDC-0810 Single Agent and Its Glucuronide Metabolites
timeFrame: 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
measure: Phase Ia: Area Under the Concentration-time Curves at 24 Hours (AUC0-24) of GDC-0810 Single Agent and Its Glucuronide Metabolites
timeFrame: 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
measure: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-Inf)
timeFrame: Day-7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours postdose
measure: Phase Ia: Plasma Half-life (t1/2) of GDC-0810 Single Agent
timeFrame: Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose
measure: Phase Ia: Apparent Clearance (Cl/F)
timeFrame: Day -7 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48 hours postdose
measure: Phase IIa: Effect of GDC-0810 Single Agent on Ventricular Repolarization as Measured by Corrected QT Intervals (QTc) Using Fridericia's Formula
timeFrame: 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
measure: Phase Ib: Cmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
timeFrame: 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
measure: Phase Ib: Tmax of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
timeFrame: 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
measure: Phase Ib: AUC0-6 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
timeFrame: 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
measure: Phase Ib: t/2 of GDC-0810 in Combination With Palbociclib and/or an LHRH Agonist
timeFrame: 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
measure: Phase Ib: Cmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
timeFrame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Phase Ib: Tmax of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
timeFrame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Phase Ib: AUC0-6 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
timeFrame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Phase Ib: t/2 of Palbociclib in Combination With GDC-0810 and/or an LHRH Agonist
timeFrame: Cohort C1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 1 Day 8
measure: Phase Ib: Cmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib
timeFrame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
measure: Phase Ib: Tmax of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib
timeFrame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
measure: Phase Ib: AUC0-6 of LHRH Agonist in Combination With GDC-0810 and/or an Palbociclib
timeFrame: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
measure: Phase Ib: t/2 of LHRH Agonist in Combination With GDC-0810 and/or Palbociclib
timeFrame: Cohort D1: Predose and at 1, 2, 3, 4, and 6 hours postdose on Cycle 1 Day 1 and Cycle 2 Day 1
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Ucsd Medical Center
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital.
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Mount SInai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Amsterdam
country: Netherlands
facility: VU MEDISCH CENTRUM; Dept. of Medical Oncology
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.