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

Roche

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Breast Neoplasms

Treatments: Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody; Drug: Bevacizumab; Drug: Fulvestrant; Drug: Entinostat; Drug: Exemestane; Drug: Abemaciclib; Drug: Ipatasertib; Drug: Tamoxifen

Study type: Interventional

Funder types: Industry

Identifiers

NCT03280563

CO39611

2017-000335-14 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 138 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

---

138 participants in 8 patient groups

Stage 1: Fulvestrant

Active Comparator group

Description:

Participants will receive fulvestrant until unacceptable toxicity or disease progression according to RECIST v1.1.

Treatment:

Drug: Fulvestrant

Stage 1: Atezolizumab + Entinostat

Experimental group

Description:

Participants will receive doublet combination treatment with atezolizumab plus entinostat until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Treatment:

Drug: Entinostat

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Stage 1: Atezolizumab + Fulvestrant

Experimental group

Description:

Participants will receive doublet combination treatment with atezolizumab plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Treatment:

Drug: Fulvestrant

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Stage 1: Atezolizumab + Ipatasertib

Experimental group

Description:

Participants will receive doublet combination treatment with atezolizumab plus ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.

Treatment:

Drug: Ipatasertib

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Stage 1: Atezolizumab + Ipatasertib + Fulvestrant

Experimental group

Description:

Participants will receive triplet combination treatment with atezolizumab plus ipatasertib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Prior to enrollment into this arm, the first 6 participants in the study will complete a safety run-in with atezolizumab plus ipatasertib.

Treatment:

Drug: Ipatasertib

Drug: Fulvestrant

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Stage 2: Atezolizumab + Bevacizumab + Endocrine Therapy

Experimental group

Description:

Those who progress or experience unacceptable toxicity during treatment in Stage 1 may be eligible to enter Stage 2. Participants will receive triplet combination therapy with atezolizumab plus bevacizumab plus one of three endocrine therapies (fulvestrant, exemestane, or tamoxifen) selected by the physician. Treatment in Stage 2 will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Treatment:

Drug: Tamoxifen

Drug: Exemestane

Drug: Fulvestrant

Drug: Bevacizumab

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Stage 1: Mandatory On-Treatment Biopsy

Experimental group

Description:

For experimental combination arms that demonstrate clinical activity during the preliminary phase, the Sponsor may open enrollment into a separate mandatory on-treatment biopsy cohort for that combination.

Treatment:

Drug: Ipatasertib

Drug: Abemaciclib

Drug: Entinostat

Drug: Fulvestrant

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody

Stage 1: Atezolizumab + Abemaciclib + Fulvestrant

Experimental group

Description:

Participants will receive triplet combination treatment with atezolizumab plus abemaciclib plus fulvestrant until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Treatment:

Drug: Abemaciclib

Drug: Fulvestrant

Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody