A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer

Breast Neoplasms Clinical Trial

— MORPHEUS HR+BC  

Official title:

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Hormone Receptor-Positive HER2-Negative Breast Cancer (MORPHEUS-HR+ Breast Cancer)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03280563
• Other study ID #: CO39611
• Secondary ID: 2017-000335-14
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: December 26, 2017
• Est. completion date: December 31, 2024

Study information

• Verified date: June 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 138
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria for Both Stages:

• Measurable disease per RECIST v1.1

• Adequate hematologic and end organ function

• Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor

Inclusion Criteria for Stage 1:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Metastatic or inoperable, locally advanced, histologically or cytologically confirmed invasive HR-positive HER2-negative breast cancer

• Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study entry

• Recurrence or progression following most recent systemic breast cancer therapy

• Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease

• Postmenopausal according to protocol-defined criteria

• Life expectancy >3 months

• Available tumor specimen for determination of PD-L1 status

Inclusion Criteria for Stage 2:

• ECOG performance status of 0-2

• Ability to initiate treatment within 3 months after disease progression or unacceptable toxicity on a Stage 1 regimen

Exclusion Criteria for Both Stages:

• Significant or uncontrolled comorbid disease as specified in the protocol

• Uncontrolled tumor-related pain

• Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes mellitus, or certain dermatologic conditions

• Positive human immunodeficiency virus test

• Active hepatitis B or C

• Active tuberculosis

• Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study treatment

• Prior allogeneic stem cell or solid organ transplantation

• History of malignancy other than breast cancer within 2 years prior to screening except those with negligible risk of metastasis/death

• History of or known hypersensitivity to study drug or excipients

• For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent

Exclusion Criteria for Stage 1:

• Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain other agents as specified in the protocol

• Unresolved AEs from prior anti-cancer therapy

• Eligibility only for the control arm

• Prior treatment with inhibitors as specified in the protocol

Exclusion Criteria for Stage 2:

• Unacceptable toxicity with atezolizumab during Stage 1

• Uncontrolled cardiovascular disease or coagulation disorder, including use of anticoagulants as specified in the protocol

• Significant abdominal or intestinal manifestations within 6 months prior to treatment

• Grade 2 or higher proteinuria

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

Drug:
• Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
Atezolizumab will be given as 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. This regimen will apply to all arms except when given with entinostat in Stage 1, or exemestane or tamoxifen in Stage 2, in which atezolizumab will be given as 1200 mg via IV infusion on Day 1 of each 21-day cycle.
• Bevacizumab
Bevacizumab will be given as 10 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 15 of each 28-day cycle in the regimen containing fulvestrant. When given with exemestane or tamoxifen, bevacizumab will be given as 15 mg/kg via IV infusion on Day 1 of each 21-day cycle.
• Entinostat
Entinostat will be given as 5 mg orally once a week on Days 1, 8 and 15 of each 21-day cycle.
• Exemestane
Exemestane will be given as 25 mg orally QD in each 21-day cycle.
• Fulvestrant
Fulvestrant will be given as 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and thereafter on Day 1 of each 28-day cycle.
• Ipatasertib
Ipatasertib will be given as 400 mg orally QD on Days 1-21 of each 28-day cycle.
• Tamoxifen
Tamoxifen will be given as 20 mg orally QD in each 21-day cycle.
• Abemaciclib
Abemaciclib will be given as 150mg twice daily during each 28-day cycle.

Locations

Country	Name	City	State
Israel	Rambam Medical Center	Haifa
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Rabin Medical Center-Beilinson Campus; Davidof Institute	Petach Tikva
Israel	Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center; Pharmacy	Tel Aviv
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	University of Ulsan College of Medicine - Asan Medical Center	Seoul
United States	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Rush University Medical Center - Chicago	Chicago	Illinois
United States	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UPMC Pinnacle Health System	Harrisburg	Pennsylvania
United States	Houston Methodist Hospital; Department of Pharmacy	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Northwest Georgia Oncology Centers PC - Marietta	Marietta	Georgia
United States	SCRI Oncology Partners	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Univ of Pittsburgh Sch of Med; Magee-Womens Hospital	Pittsburgh	Pennsylvania
United States	Providence Cancer Center	Portland	Oregon
United States	UCSF Helen Diller Family CCC	San Francisco	California
United States	Stanford Cancer Institute	Stanford	California
United States	Northwest Medical Specialties, PLLC; Research Department	Tacoma	Washington
United States	Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center	Torrance	California
United States	Wellness Oncology and Hematology - Main Office	West Hills	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Israel,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1		From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
Secondary	Progression-Free Survival during Stage 1 According to RECIST v1.1		From randomization until disease progression or death from any cause (up to 6 years overall)
Secondary	Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1		From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
Secondary	Overall Survival during Stage 1		From randomization until death from any cause (up to 6 years overall)
Secondary	Percentage of Participants Alive at 18 Months during Stage 1		18 months
Secondary	Duration of Response during Stage 1 According to RECIST v1.1		From first objective response until disease progression or death from any cause (up to 6 years overall)
Secondary	Percentage of Participants with Adverse Events (AEs) during Stage 1		From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
Secondary	Percentage of Participants with AEs during Stage 2		From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
Secondary	Atezolizumab Serum Concentration during Stage 1		Predose (0 hours [h]) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Secondary	Entinostat Serum and Plasma Concentration during Stage 1		Serum predose (0 h) and plasma postdose (2-4 h) on Day 1 of Cycle 1; plasma predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
Secondary	Fulvestrant Plasma Concentration during Stage 1		Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Secondary	Ipatasertib Plasma Concentration during Stage 1		Predose (0 h) and postdose (1, 2, 4, 6 h) on Day 15 of Cycle 1; postdose (1-3 h) on Day 15 of Cycle 3
Secondary	Atezolizumab Serum Concentration during Stage 2		Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); postdose (30 min) (infusion = 30-60 min) on Day 1 of Cycle 1; at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Secondary	Bevacizumab Serum Concentration during Stage 2		Predose (0 h) and postdose (30 min) (infusion = 30-90 min) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Secondary	Exemestane Plasma Concentration during Stage 2		Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
Secondary	Fulvestrant Plasma Concentration during Stage 2		Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
Secondary	Tamoxifen Plasma Concentration during Stage 2		Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
Secondary	Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1		Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Secondary	Percentage of Participants with ADAs to Atezolizumab during Stage 2		Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Secondary	Percentage of Participants with ADAs to Bevacizumab during Stage 2		Predose (0 h) on Day 1 of Cycles 1, 3 (cycle = 21-28 days); at treatment discontinuation (up to 6 years); and 120 days after last dose (up to 6 years overall)
Secondary	Abemaciclib Plasma Concentration during Stage 1		Predose (0 h), Postdose (30 minutes post infusion), and 4-8 hours after dose on Day 1 Cycle 1; Predose on Day 15 Cycle 1 and Day 1 of Cycles 2 and 3