Inoperable, Locally Advanced or Metastatic, ER-positive Breast Cancer
Conditions
Brief summary
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.
Interventions
DRUGGiredestrant
30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression
DRUGAbemaciclib
150 mg orally twice a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression
DRUGIpatasertib
400 mg orally once a day on Days 1-21 of each 28-day cycle until unacceptable toxicity or disease progression
DRUGInavolisib
9 mg orally once a day during each 28-day cycle until unacceptable toxicity or disease progression
DRUGRibociclib
600 mg orally once a day on Days 1-21 of each 28-day cycle until unacceptable toxicity or disease progression
DRUGEverolimus
10 mg orally once a day during each 28-day cycle until unacceptable toxicity or disease progression
DRUGSamuraciclib
360 mg orally once a day during each 28-day cycle until unacceptable toxicity or disease progression
DRUGPH FDC SC
On Day 1 of Cycle 1 (1 cycle is 21 days), pertuzumab and trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) will be administered SC as a fixed dose formulation of 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase. On Day 1 of Cycles 2 and beyond, PH FDC SC will be administered SC once every 21 days as a fixed dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase.
DRUGPalbociclib
125 mg orally once a day on Days 1-21 during each 28-day cycle until unacceptable toxicity or disease progression
DRUGAtezolizumab
840 mg by intravenous (IV) infusion on Days 1 and 15 each 28-day cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for Cohort 1 (Stage 1 \[and Stage 2, only where indicated\]): * 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 Inclusion Criteria for Cohort 2 (Stage 1 \[and Stage 2, only where indicated\]): * 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 Inclusion Criteria for Cohorts 1 and 2 (Stage 2): * 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 Inclusion Criteria for Cohort 3: * 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 * Evidence of an eligible PIK3CA mutation based on pre-existing test results (i.e., previously 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 to determine PIK3CA mutation status at a central testing site with the FoundationOne Liquid® CDx assay is required.
Exclusion criteria
General
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants with Objective Response, Defined as a Complete or Partial Response, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) | From Baseline until disease progression (up to 6 years) |
| Number of Participants with Adverse Events, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) | From Baseline until 30 days after the last dose of study drug (up to 6 years) |
Secondary
| Measure | Time frame |
|---|---|
| Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1 | From randomization to the date of the first recorded occurrence of disease progression or death from any cause, whichever occurs first (up to 6 years) |
| Disease Control Rate, Defined as the Percentage of Participants with Stable Disease for ≥12 Weeks or a Complete or Partial Response, as Determined by the Investigator According to RECIST v1.1 | From Baseline until disease progression (up to 6 years) |
| Clinical Benefit Rate, Defined as the Percentage of Participants with Stable Disease for ≥24 Weeks or with Confirmed Complete or Partial Response, as Determined by the Investigator According to RECIST v1.1 | From Baseline until disease progression (up to 6 years) |
| Overall Survival | From randomization to death from any cause (up to 6 years) |
| Duration of Response, as Determined by the Investigator According to RECIST v1.1 | From first occurrence of a document objective response to the first date of recorded disease progression or death from any cause, whichever occurs first (up to 6 years) |
Countries
Australia, Israel, South Korea, Spain, United States
Contacts
CONTACTReference Study ID Number: CO42867 https://forpatients.roche.com/
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed