Trial of 225Ac-DOTATATE (RYZ101) in Subjects With ER+, HER2-negative Unresectable or Metastatic Breast Cancer Expressing SSTRs.

Subjects must meet all the following criteria for enrollment in the study:

• Histologically confirmed, ER+, HER2-negative, locally advanced and unresectable or metastatic breast cancer not amenable to treatment with curative intent.
• Adequate renal, hematologic, and hepatic function
• Additional inclusion criteria for Monotherapy arm:
  • Measurable disease with at least 80% SSTR-positive lesions by SSTR-PET imaging
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  • Documented radiologic progression after at least 2 and no more than 4 prior chemotherapy or ADC regimens in the metastatic setting
• Additional inclusion criteria for ET Combination arms:
  • Prior treatment with CDK4/6 inhibitors in combination with endocrine therapy in the advanced or metastatic setting.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤1
  • Bone only or bone dominant disease. At least 1 bone lesion must be SSTR-positive on SSTR-PET imaging. For bone dominant disease, at least 50% of soft tissue measurable lesions must be SSTR-positive on SSTR-PET imaging. At least one bone lesion must be positive on both SSTR-PET and on FDG-PET imaging
  • Brain metastases are allowed if definitively treated and clinically stable as confirmed by interval imaging

Subjects who meet any of the following criteria will be excluded from the study:

• Prior radiopharmaceutical therapy, including radioembolization.
• Any toxicities from prior treatments that have not recovered to CTCAE Grade ≤1, except for alopecia.
• Significant cardiovascular disease
• Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, spinal cord compression, or leptomeningeal disease.
• History of hypersensitivity or allergy to 225Ac, 68Ga, 64Cu, octreotate, or any of the excipients of DOTATATE imaging agents.
• Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the study safety or efficacy assessments.
• Pregnancy or breastfeeding
• Additional exclusion criteria for ET Combination arms:
  • Presence of liver metastases or symptomatic metastatic visceral disease
  • Prior PARPi exposure or are candidates for PARPi per local guidelines