Clinical trial NCT03332797: A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer
Official title: A Phase Ia/Ib, Multicenter, Open-Label, Dose Escalation, Dose Expansion Study Evaluating the Safety, Pharmacokinetics, and Activity of GDC-9545 Alone or in Combination With Palbociclib and/or LHRH Agonist in Patients With Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Breast Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2017-11-06
Enrollment: 181
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent and in combination with palbociclib and/or luteinizing hormone-releasing hormone (LHRH) agonist in participants with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 \[HER2\]-negative) breast cancer.


Eligibility criteria: Inclusion Criteria for Dose Escalation:

* 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 with metastatic disease
* Estrogen receptor (ER)-positive tumor
* Human epidermal growth factor receptor 2 (HER2)-negative breast cancer as per local laboratory testing
* Measurable disease, or evaluable bone disease; that is, bone lesions that are lytic or mixed (lytic + sclerotic) in the absence of measurable lesion
* Required paired pre- and on-treatment tumor biopsies for participants with metastases that are safely accessible as determined by the investigator
* Advanced or metastatic ER-positive/HER2-negative breast cancer that has recurred or progressed while being treated with adjuvant endocrine therapy for a duration of at least 24 months and/or endocrine therapy in the incurable, locally advanced, or metastatic setting and derived a clinical benefit from therapy (i.e., tumor response or stable disease for at least 6 months)
* No more than 2 prior lines of treatment for advanced or metastatic breast cancer
* Greater than or equal to (≥)2 weeks must have elapsed from the use of any other endocrine, targeted therapy or chemotherapy
* Single-Agent Cohorts (only applies to Dose Escalation): Advanced or metastatic disease that is either refractory to or intolerant of existing standard therapy or for which no effective standard therapy that confers clinical benefit is available
* Cohort B0: No prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor
* For participants undergoing 18F-fluoroestradiol-positron emission tomography (FES-PET) imaging additional restrictions on prior therapy include: ≥2 months must have elapsed from the use of tamoxifen; ≥6 months must have elapsed from the use of fulvestrant
* Postmenopausal status
* Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (≤)1
* Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or Grade ≤1 (except alopecia or other toxicities not considered to be a safety risk for the patient)
* Life expectancy of ≥12 weeks
* Adequate organ function

Inclusion Criteria for Dose Expansion:

Same criteria as above for Dose Escalation, except for those that only apply to Dose Escalation, plus the following:

* Required paired pre- and on-treatment tumor biopsies for participants in Cohorts A1-A5, B1, and B2 with metastases that are safely accessible as determined by the investigator
* In South Korea: Must have received exactly 2 prior lines of treatment for advanced or metastatic breast cancer
* In the rest of the world: No more than 1 prior line of treatment for advanced or metastatic breast cancer (not applicable to Cohort X)

Plus the following criteria:

* Cohorts B1 and B2: No prior treatment with CDK4/6 inhibitor
* Cohorts A1, A3, A5, B1, C1, and C2 only: Postmenopausal status
* Cohorts A2, A4, and B2 only: Participants not defined as postmenopausal; Age less than (\<)56 years who have medical menopause on LHRH agonist (on stable dose ≥4 weeks)
* No prior treatment with an oral selective estrogen receptor degrader (SERD)
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use non-hormonal contraceptive methods with a failure rate of \<1% per year during the treatment period and for 10 days after the last dose of GDC-9545 and 21 days after the last dose of palbociclib, and agreement to refrain from donating eggs during this same period
* Cohort X only: Participants enrolled on Studies GO29656 or GO29642 and received clinical benefit from GDC-0927 or GDC-0810
* Hematology, chemistry, and urinalysis collected 72 hours before Cycle 1, Day 1 deemed acceptable for dosing by the investigator
* No other endocrine therapy, targeted therapy, or chemotherapy after last dose of GDC-0927 or GDC-0810

Exclusion Criteria for Dose Escalation:

* Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
* Current treatment with any systemic anti-cancer therapies for advanced disease (not applicable to Cohort X participants currently receiving GDC-0810 or GDC-0927)
* Concurrent treatment with warfarin or phenytoin
* Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
* Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
* Known human immunodeficiency virus (HIV) infection
* Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis
* Major surgery within 4 weeks prior to enrollment
* Radiation therapy within 2 weeks prior to enrollment
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
* Inability or unwillingness to swallow tablets or capsules (only applies to Dose Escalation)
* Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study (only applies to Dose Escalation)
* History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction
* QT interval corrected using Fridericia's formula (QTcF) greater than (\>)470 milliseconds (ms) demonstrated by at least two ECGs \>30 minutes apart
* History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease coronary heart disease clinically significant electrolyte abnormalities or family history of sudden unexplained death or long QT syndrome
* Current treatment with medications that are well known to prolong the QT interval

Exclusion Criteria for Dose Expansion:

Same criteria as above for Dose Escalation, except for those that only apply to Dose Escalation, plus the following criteria:

* Pregnant, lactating, or breastfeeding
* Additional exclusion criteria for Cohort B (Phase 1b cohort): History of venous thromboembolic event requiring therapeutic anticoagulation
* Additional exclusion criteria for Cohorts C1 and C2 only: Current treatment with medications that are well known to decrease heart rate, including beta blockers

Primary outcomes:
measure: Number of Participants with Adverse Events by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0)
timeFrame: From Baseline until 28 days after the last dose of study treatment (up to 84 months)
measure: Dose Escalation: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of GDC-9545 When Administered as a Single Agent or in Combination with Palbociclib
timeFrame: Days -7 to 28 of Cycle 1
measure: Dose Escalation: Number of Participants with Dose-Limiting Toxicities When GDC-9545 is Administered as a Single Agent or in Combination with Palbociclib
timeFrame: Days -7 to 28 of Cycle 1
measure: Change from Baseline in Systolic Blood Pressure Over Time
timeFrame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment
measure: Change from Baseline in Diastolic Blood Pressure Over Time
timeFrame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment
measure: Change from Baseline in Body Temperature Over Time
timeFrame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment
measure: Change from Baseline in Pulse Rate Over Time
timeFrame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment
measure: Change from Baseline in Respiration Rate Over Time
timeFrame: Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment
measure: Change from Baseline in Electrocardiogram (ECG) Results Over Time: Heart Rate
timeFrame: Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment
measure: Change from Baseline in ECG Results Over Time: PR Duration
timeFrame: Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment
measure: Change from Baseline in ECG Results Over Time: QRS Duration
timeFrame: Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment
measure: Change from Baseline in ECG Results Over Time: QT Duration
timeFrame: Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment
measure: Change from Baseline in ECG Results Over Time: QTcF Duration
timeFrame: Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment
measure: Change from Baseline in ECG Results Over Time: RR Duration
timeFrame: Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment
measure: Number of Participants with Clinical Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v4.0
timeFrame: Baseline, Cycle 1, and at each subsequent cycle (1 cycle is 28 days) or at every other cycle starting from Cycle 3 (Cohort X only), up to 28 days after the last dose of study treatment
measure: Number of Participants with Clinical Laboratory Abnormalities in Blood Chemistry Tests by Highest Grade According to NCI-CTCAE v4.0
timeFrame: Baseline, Cycle 1, and at each subsequent cycle (1 cycle is 28 days) or at every other cycle starting from Cycle 3 (Cohort X only), up to 28 days after the last dose of study treatment
measure: Number of Participants with Clinical Laboratory Abnormalities in Urinalysis Tests by Highest Grade According to NCI-CTCAE v4.0
timeFrame: Baseline, Cycle 3, and at every other cycle (1 cycle is 28 days) up to 28 days after the last dose of study treatment
Secondary outcomes:
measure: Plasma Concentration of GDC-9545 Over Time
timeFrame: At predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation and A1-A5 only) or Cycle 1, Day 1 (B0, B1, and B2) to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion; Cycle 1, Days -7 or 8 (C1 only); Cycle 1, Day 8 (C2 only)
measure: Plasma Concentration of Palbociclib Over Time
timeFrame: At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B0, B1, and B2 only); Cycle 1, Day 8 (C2 only)
measure: Plasma Concentration of LHRH Over Time
timeFrame: At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B2 only)
measure: Percentage of Participants with Objective Response
timeFrame: For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 84 months)
measure: Clinical Benefit Rate
timeFrame: For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 84 months)
measure: Duration of Response
timeFrame: For all cohorts, except for Cohort X: From the first occurrence of a documented objective response until first observation of disease progression or death from any cause on study, whichever occurs first (up to 84 months)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital.
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
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: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
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: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO L'Hospitalet
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Quiron Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Centro Oncologioco MD Anderson Internacional
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: Suttton
country: United Kingdom
facility: The Royal Marsden Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: