Clinical trial NCT03280563: A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Neoplasms
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-09-12
Enrollment: 138
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants with Objective Response during Stage 1 According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
timeFrame: From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
Secondary outcomes:
measure: Progression-Free Survival during Stage 1 According to RECIST v1.1
timeFrame: From randomization until disease progression or death from any cause (up to 6 years overall)
measure: Percentage of Participants with Clinical Benefit during Stage 1 According to RECIST v1.1
timeFrame: From baseline until disease progression or loss of clinical benefit (up to 6 years overall)
measure: Overall Survival during Stage 1
timeFrame: From randomization until death from any cause (up to 6 years overall)
measure: Percentage of Participants Alive at 18 Months during Stage 1
timeFrame: 18 months
measure: Duration of Response during Stage 1 According to RECIST v1.1
timeFrame: From first objective response until disease progression or death from any cause (up to 6 years overall)
measure: Percentage of Participants with Adverse Events (AEs) during Stage 1
timeFrame: From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
measure: Percentage of Participants with AEs during Stage 2
timeFrame: From baseline until 30 days after last dose or initiation of new systemic anti-cancer therapy (up to 6 years overall)
measure: Atezolizumab Serum Concentration during Stage 1
timeFrame: 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)
measure: Entinostat Serum and Plasma Concentration during Stage 1
timeFrame: 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)
measure: Fulvestrant Plasma Concentration during Stage 1
timeFrame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
measure: Ipatasertib Plasma Concentration during Stage 1
timeFrame: 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
measure: Atezolizumab Serum Concentration during Stage 2
timeFrame: 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)
measure: Bevacizumab Serum Concentration during Stage 2
timeFrame: 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)
measure: Exemestane Plasma Concentration during Stage 2
timeFrame: Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
measure: Fulvestrant Plasma Concentration during Stage 2
timeFrame: Predose (0 h) on Day 1 of Cycles 2-3 (cycle = 28 days)
measure: Tamoxifen Plasma Concentration during Stage 2
timeFrame: Predose (0 h) on Day 1 of Cycle 2 (cycle = 21 days)
measure: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab during Stage 1
timeFrame: 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)
measure: Percentage of Participants with ADAs to Atezolizumab during Stage 2
timeFrame: 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)
measure: Percentage of Participants with ADAs to Bevacizumab during Stage 2
timeFrame: 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)
measure: Abemaciclib Plasma Concentration during Stage 1
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family CCC
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
state: California
city: West Hills
country: United States
facility: Wellness Oncology and Hematology - Main Office
state: California
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers PC - Marietta
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center - Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Cancer Center
state: Oregon
city: Harrisburg
country: United States
facility: UPMC Pinnacle Health System
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh Sch of Med; Magee-Womens Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute / Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Hospital; Department of Pharmacy
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialties, PLLC; Research Department
state: Washington
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Petach Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus; Davidof Institute
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center; Pharmacy
city: Goyang-si
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: University of Ulsan College of Medicine - Asan Medical Center
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: