Tuberous Sclerosis Complex Clinical Trials

• Sex and Age: Patients must be ≥ 18 years of age at the time of informed consent.

‣ Cohort A (HR+/HER2- breast cancer): Eligible patients must be postmenopausal women, defined as women ≥ 18 years of age with amenorrhea for ≥ 12 consecutive months without another pathophysiological cause.

⁃ Cohort B (RCC, NETs, TSC-associated tumors, HCC): Eligible patients include both male and female adults with advanced disease.

• Cohort A HR+/HER2- Breast Cancer:

• Eligible patients must meet all of the following:

⁃ Has histologically or cytologically documented advanced (metastatic or unresectable) hormone receptor-positive, HER2 negative breast cancer (advanced HR+ BC)

⁃ Has stage IV or locally advanced breast cancer per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Seventh Edition;

⁃ Has failed any combination endocrine therapy or relapse within 6 months of adjuvant chemotherapy for metastatic or locally advanced disease. Prior therapy should have included a non-steroidal aromatase inhibitor unless clinically contraindicated;

⁃ Has agreed to participate in the study and signed the informed consent form prior to participation in any study activities.

• Cohort B Other Advanced mTOR-Sensitive Solid Tumors:

• Eligible patients must meet all of the following:

⁃ Has histologically or cytologically confirmed advanced (metastatic or unresectable) disease in one of the following tumor types:

• Renal Cell Carcinoma (RCC)

∙ Neuroendocrine Tumors (NETs)

∙ Tuberous Sclerosis Complex (TSC)-associated tumors

∙ Hepatocellular Carcinoma (HCC)

⁃ Has disease that is measurable and/or evaluable per RECIST v1.1 (or relevant criteria, if applicable).

⁃ Has progressed on or is intolerant to at least one prior line of standard therapy appropriate for the specific tumor type, unless no effective standard therapy exists.

⁃ Has agreed to participate in the study and signed the informed consent form prior to participation in any study activities.

• Patients must be on stable doses of metformin or statin

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• Life expectancy ≥ 3 months

• Hematology/chemistry: Patient has adequate hematological, renal, and hepatic function as defined by the following Screening laboratory values obtained within 7 days prior to randomization and assessed based on local labs (patients should not have received a transfusion within 7 days before the Screening laboratory assessments):

‣ Absolute neutrophil count (ANC) ≥ 2,000 cells/mm3 (2 x109/L)

⁃ Platelet count ≥ 100,000 cells/mm3 (100x109/L)

⁃ Hemoglobin≥ 9 g/dL

⁃ Serum creatinine≤ 1.5 x the upper limit of normal (ULN)

⁃ Total bilirubin ≤1.5 x ULN or direct bilirubin ≤1 x ULN for patients with total bilirubin levels \> 1.5 ULN

⁃ AST (SGOT) / ALT (SGPT) ≤ 2.5 x ULN (≤5 x ULN for patients with metastases.)

⁃ GFR ≥ 50 mL/min/1.73m2 by the CKD-EPI or MDRD formulas.

• All other clinical laboratory values deemed as normal or not clinically significant by the Principal Investigator/Sub-Investigator.

• Breastfeeding: Patients must be non-lactating. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding must be discontinued prior to the first dose of study drug.

⁃ Female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during the study and for 8 weeks after the last dose. Male patients with female partners of reproductive potential to use effective contraception during the study and for 4 weeks after the last dose.

⁃ Able and willing to adhere to all protocol requirements and study procedures throughout the course of the study.

⁃ Ability to comprehend and be informed of the nature of the study, as assessed by study clinic staff