A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer

• Status: Recruiting
• Trial end date: 2027-04-30
• Target enrollment: 0
• Participant gender: Female

Summary

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with breast cancer. The current cohort (Cohort 1) will focus on participants with inoperable, locally advanced or metastatic, estrogen receptor (ER)-positive 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. 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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Hoffmann-La Roche
• Treatments: Everolimus

Criteria

Inclusion Criteria:

Inclusion Criteria for Cohort 1:

• 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 evaluation of Ki67, and/or additional biomarkers via central testing

• Prior fulvestrant therapy is allowed

• Measurable disease

• Adequate hematologic and end-organ function

• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

Exclusion Criteria:

General Exclusion Criteria for Cohort 1:

• Known HER2-positive breast cancer

• Prior treatment with cytotoxic chemotherapy for metastatic breast cancer

• Concurrent hormone replacement therapy

• Prior treatment with any of the protocol-specified study treatments

• Treatment with investigational therapy within 28 days prior to initiation of study treatment

• Systemic treatment for ER+ breast cancer within 2 weeks of Cycle 1, Day 1 or 5 half-lives of the drug prior to Cycle 1, Day 1

• Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤1 or better, with the exception of alopecia of any grade and Grade ≤2 peripheral neuropathy

• Prior allogeneic stem cell or solid organ transplantation

• Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study

• History of malignancy other than breast cancer within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures

• Uncontrolled tumor-related pain

• Uncontrolled or symptomatic hypercalcemia

• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases

• History of leptomeningeal disease

• Active tuberculosis

• Severe infection within 4 weeks prior to initiation of study treatment

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan

• Active cardiac disease or history of cardiac dysfunction

• Positive HIV test at screening or at any time prior to screening

• Active Hepatitis B or Hepatitis C virus infection

• Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery, including gastric resection, potentially affecting enteral absorption

• Known allergy or hypersensitivity to any of the study drugs or any of their excipients

Giredestrant + Ipatasertib Arm Exclusion Criteria:

• Prior treatment with an Akt inhibitor

• Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceremia

• History of Type 1 or Type 2 diabetes mellitus requiring insulin

• Congenital long QT syndrome or screening QTcF >480 milliseconds

• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion

• Treatment with strong CYP3A4 inducers and inhibitors within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

Giredestrant + Abemaciclib Arm Exclusion Criteria:

• Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy

• History of major surgical resection involving the stomach or small bowel, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea

• History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest

Giredestrant + Inavolisib Arm Exclusion Criteria:

• Prior treatment with any PI3K, Akt, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway

• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes

• Fasting glucose ≥126 mg/dL or ≥7.0 mmol/L and HbA1c ≥5.7%

• Any concurrent ocular or intraocular condition that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition

• Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye

• Symptomatic active lung disease, including pneumonitis

• Inability to confirm biomarker eligibility based on valid results from either central testing of blood or local testing of blood or tumor tissue that documents one of the protocol-defined PIK3CA mutations

Giredestrant + Ribociclib Arm Exclusion Criteria:

• Currently receiving any of the following substances within 7 days before randomization: concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5

• Currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting trial treatment

• Impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments