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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

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ClinicalTrials.gov Identifier: NCT03332797
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : November 20, 2018
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

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 patients with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 [HER2]-negative) breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: GDC-9545 Drug: Palbociclib Drug: LHRH agonist Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 27, 2017
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Dose Escalation: GDC-9545
During dose escalation, participants will be assigned sequentially to escalating doses of GDC-9545, up to the maximum tolerated dose (MTD) or maximum administered dose (MAD).
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Experimental: Dose Escalation: Cohort B0: GDC-9545 + Palbociclib
GDC-9545 will be administered at a dose lower than the MTD or MAD determined in single-agent dose escalation along with the label-recommended dose of Palbociclib.
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Drug: Palbociclib
Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Experimental: Dose Expansion: Cohort A1: GDC-9545 Dose 1
GDC-9545 will be administered as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 1).
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Experimental: Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD (Dose 1) along with an approved LHRH agonist.
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Drug: LHRH agonist
LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. Physician will choose LHRH agonist approved for use in breast cancer.

Experimental: Dose Expansion: Cohort A3: GDC-9545 Dose 2
GDC-9545 will be administered as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 2).
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Experimental: Dose Expansion: Cohort A4; GDC-9545 Dose 2 + LHRH
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD (Dose 2) along with an LHRH agonist.
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Drug: LHRH agonist
LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. Physician will choose LHRH agonist approved for use in breast cancer.

Experimental: Dose Expansion: Cohort B1: GDC-9545 + Palbociclib
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD along with Palbociclib.
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Drug: Palbociclib
Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Experimental: Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD along with Palbociclib and an approved LHRH agonist.
Drug: GDC-9545
GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Drug: Palbociclib
Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).

Drug: LHRH agonist
LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. Physician will choose LHRH agonist approved for use in breast cancer.




Primary Outcome Measures :
  1. Percentage of Participants with Adverse Events [ Time Frame: From baseline through end of study (up to 21 months) ]
  2. Maximum Tolerated Dose (MTD) of GDC-9545 When Used as a Single Agent [ Time Frame: Days -7 to 28 of Cycle 1 ]

Secondary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of GDC-9545 Administered as a Single Agent [ Time Frame: At predefined intervals from Cycle 1, Day -7 through Cycle 4, Day 1 (4 months) ]
  2. Maximum Observed Plasma Concentration (Cmax) of GDC-9545 Administered in Combination [ Time Frame: At predefined intervals from Cycle 1, Day 1 through Cycle 4, Day 1 (4 months) ]
  3. Objective Response [ Time Frame: Baseline; Every 8 weeks from Cycle 1, Day 1 to end of study (up to 21 months) ]
  4. Clinical Benefit Rate Assessed by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v 1.1) [ Time Frame: From baseline to end of study (up to 21 months) ]
  5. Duration of Response (DOR) [ Time Frame: From the first occurrence of a documented objective response to the first observation of disease progression or death from any cause through the end of study (up to 21 months) ]
  6. Maximum Observed Plasma Concentration (Cmax) of Palbociclib [ Time Frame: At predefined intervals from Cycle 1, Day 1 through Cycle 4, Day 1 (4 months) ]
  7. Maximum Observed Plasma Concentration (Cmax) of LHRH [ Time Frame: At predefined intervals from Cycle 1, Day 1 through Cycle 4, Day 1 (4 months) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  • ER-positive tumor
  • 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
  • ≥ 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 (CDK) 4/6 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 ≤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 as above, except:

  • 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 one prior line of treatment for advanced or metastatic breast cancer

And plus:

  • Cohort B1−2: No prior treatment with CDK4/6 inhibitor
  • Cohorts A1, A3, and B1 only: Postmenopausal status
  • Cohorts A2, A4, and B2 only: Participants not defined as post-menopausal
  • 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 40 days after the last dose of GDC-9545, and agreement to refrain from donating eggs

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
  • 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 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

Exclusion Criteria for Dose Expansion:

Same as above, plus:

  • Pregnant, lactating, or breastfeeding
  • Additional exclusion criteria for participants in Cohort B: History of venous thromboembolic event requiring therapeutic anticoagulation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03332797


Contacts
Contact: Reference Study ID Number: GO39932 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. Only) global-roche-genentech-trials@gene.com

Locations
United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045
United States, Massachusetts
Massachusetts General Hospital. Recruiting
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
United States, Tennessee
Vanderbilt University Medical Center; Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Australia, New South Wales
St Vincent's Hospital Sydney Recruiting
Darlinghurst, New South Wales, Australia, 2010
Australia, Victoria
Peter Maccallum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3000
Korea, Republic of
National Cancer Center; Medical Oncology Recruiting
Gyeonggi-do, Korea, Republic of, 410-769
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 03080
Severance Hospital, Yonsei University Health System; Pharmacy Recruiting
Seoul, Korea, Republic of, 03722
Asan Medical Center Recruiting
Seoul, Korea, Republic of, 05505
Samsung Medical Center Recruiting
Seoul, Korea, Republic of, 6351
Spain
ICO L'Hospitalet; Servicio de oncologia medica Recruiting
L Hospitalet De Llobregat, Barcelona, Spain, 08908
Onkologikoa; Ensayos Clinicos Recruiting
Donostia, Guipuzcoa, Spain, 20014
Hospital Quiron Barcelona; Servicio de Oncologia Recruiting
Barcelona, Spain, 08024
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain, 08035
MD Anderson Cancer Center Madrid - España; Servicio de Farmacia Recruiting
Madrid, Spain, 28033
Hospital Universitario Ramón y Cajal Recruiting
Madrid, Spain, 28034
Hospital General Universitario Gregorio Maranon Recruiting
Madrid, Spain, 28040
Hospital Universitario HM Sanchinarro; South Texas Accelerated Research Therapeutics Recruiting
Madrid, Spain, 28050
Hospital Clinico Universitario de Valencia Recruiting
Valencia, Spain, 46010
United Kingdom
Barts Health NHS Trust Not yet recruiting
London, United Kingdom, E1 2ES
The Royal Marsden NHS Foundation Trust; Oncology Not yet recruiting
London, United Kingdom, SW3 6JJ
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT03332797     History of Changes
Other Study ID Numbers: GO39932
2017-002083-41 ( EudraCT Number )
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: November 20, 2018
Last Verified: November 2018

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
Estrogens
Palbociclib
Prolactin Release-Inhibiting Factors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action