A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Breast Cancer (MORPHEUS-BREAST CANCER)
This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with breast cancer. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the patient population. Cohort 1 will focus on participants with inoperable, locally advanced or metastatic, estrogen receptor-positive (ER+), HER2-negative breast cancer who had disease progression during or following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; e.g., palbociclib, ribociclib, abemaciclib) in the first- or second-line setting. Cohort 2 will focus on inoperable, locally advanced or metastatic, ER+, HER2-positive breast cancer with previous progression to standard-of-care anti-HER2 therapies, of which one was a trastuzumab-and-taxane-based systemic therapy (including in the early setting if recurrence occurred within 6 months of finishing adjuvant therapy) and one was a HER2-targeting antibody-drug conjugate (ADC; e.g., ado-trastuzumab emtansine or trastuzumab-deruxtecan) or a HER2-targeting tyrosine kinase inhibitor (TKI; e.g., tucatinib, lapatinib, pyrotinib or neratinib). Cohort 3 will focus on inoperable, locally advanced or metastatic, ER+, HER2-negative, PIK3CA-mutated breast cancer with resistance to adjuvant endocrine therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Documented estrogen receptor-positive (ER+) tumor
• Patients for whom endocrine therapy is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatment guidelines
• Radiologic/objective evidence of recurrence or progression after the most recent systemic therapy for breast cancer
• Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease (note: at least one line of therapy must have contained a CDK4/6i administered for a minimum of 8 weeks prior to disease progression.)
• Postmenopausal status for women
• Life expectancy ≥3 months
• Availability of a representative tumor specimen that is suitable for biomarker evaluation via central testing
• Prior fulvestrant therapy is allowed
• Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1
• Stages 1 and 2: Adequate hematologic and end-organ function
• Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation
• ECOG Performance Status of 0 or 1
• Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection
• ER+, HER2-positive breast cancer
• Postmenopausal status for women
• Life expectancy ≥3 months
• Willingness to have a representative tumor specimen that is suitable for biomarker evaluation via central testing submitted, if available
• Prior endocrine therapy in the advanced setting allowed, including fulvestrant if given more than 28 days prior to randomization, but excluding other selective estrogen receptor degraders (SERDs)
• Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1
• Stages 1 and 2: Baseline left ventricular ejection fraction (LVEF) ≥50% as measured by ECHO or MUGA scans
• Stages 1 and 2: Adequate hematologic and end-organ function
• Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation
• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator, provided that a Stage 2 slot is available and patient meets eligibility criteria for Stage 2
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 because of unacceptable toxicity to drugs, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator
• Measurable disease (at least one target lesion) according to RECIST v1.1
• ECOG Performance Status of 0 or 1
• Documented ER+ tumor
• Patients for whom endocrine therapy is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatment guidelines
• Histologically or cytologically confirmed and documented adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent
• Patients must have progressed during adjuvant endocrine treatment or within 12 months of completing adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen. If a CDK4/6i was included as part of neoadjuvant or adjuvant therapy, progression event must be \>12 months since completion of CDK4/6i portion of neoadjuvant or adjuvant therapy.
• Postmenopausal status for women (including women on or starting luteinizing hormone-releasing hormone \[LHRH\] agonist for ovarian suppression prior to randomization)
• Life expectancy ≥6 months
• Adequate hematologic and end-organ function
• Confirmation of PIK3CA mutation status based on pre-existing test results (i.e., obtained as part of clinical practice) from blood or tumor tissue. If pre-existing test results are not available, submission of a freshly collected pretreatment blood sample for PIK3CA mutation status at a central testing site with the FoundationOne Liquid® CDx assay is required, outside of the E.U. In the E.U., only pre-existing test results are acceptable (central testing will not be provided).