Sapu003 in Advanced mTOR-sensitive Solid Tumors

The study will include two cohorts:

• Cohort A: Patients with HR+/HER2-negative breast cancer who will receive Sapu003 in combination with exemestane.
• Cohort B: Patients with RCC, NETs, TSC-associated tumors, or HCC who will receive Sapu003 without exemestane.

The dose levels planned for this study are 5 mg/m², 7.5 mg/m², and 10 mg/m² administered as weekly 30-minute IV infusions, with each treatment cycle lasting 4 weeks (28 days).

The primary purpose of this study is to determine the maximum tolerated dose (MTD) of weekly intravenous Sapu003. Secondary objectives include characterizing the pharmacokinetic profile of Sapu003, evaluating its safety and tolerability, and assessing preliminary antitumor activity.

Inclusion criteria

• 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

Exclusion criteria

• Patients with a history of other malignancies, except for adequately treated non-melanoma skin cancer, curatively treated in-situ carcinoma of the cervix, curatively treated in-situ carcinoma of the breast, or other solid tumors curatively treated with no evidence of disease for > 5 years.
• Patients who have not completely recovered from any toxicities from previous chemotherapy, hormone therapy, immunotherapy, target therapy, or radiotherapies ≥ Grade 1 per NCI CTCAE version 5.0, with the exception of alopecia.
• Patients who have received any of the following treatments within the specified timeframes prior to screening:

• Prior chemotherapy within 30 days prior to screening (42 days for mitomycin C or nitrosoureas).
• Prior immunotherapy, prior anti-tumor hormonal therapy (for breast cancer patients), and prior radiotherapy within 30 days prior to screening.
• Radiotherapy is not allowed during study. Administration of other chemotherapy, immunotherapy, or anti-tumor hormonal therapy during the study is not allowed.
• Patients had major surgery within 30 days prior to randomization, or patients have not recovered from prior major surgery.
• Sensory / Peripheral neuropathy of > Grade 1 per NCI CTCAE version 5.0 at Screening.
• Patients with active brain metastases. Patients with treated brain metastases are eligible provided they have no evidence of active brain disease and are off of definitive therapy (including steroids) at least 3 months prior to randomization.
• Known history or presence of any clinically significant disease or condition other than cancer unless determined as not clinically significant by the Principal Investigator/Sub-Investigator. This includes, but is not limited to, the following: hepatic, renal/genitourinary, gastrointestinal (e.g., intra-abdominal inflammation), cardiovascular (e.g., congestive heart failure, ventricular arrhythmia, myocardial infarction, unstable angina pectoris), cerebrovascular, pulmonary (e.g., interstitial lung disease), endocrine, immunological, musculoskeletal, neurological, psychiatric, dermatological, or hematological (e.g., bleeding diathesis or coagulopathy).
• History of difficulty with donating blood or difficulty in accessibility of central line.
• Known history or presence of:

• Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C (serology to confirm absence is required within 7 days prior to randomization and assessed based on local labs);
• Alcohol abuse or dependence within one year prior to randomization;
• Drug abuse or dependence (marijuana, amphetamines, barbiturates, cocaine, opiates and benzodiazepines);
• Hypersensitivity or idiosyncratic reaction to everolimus, other rapamycin derivatives or its excipients
• Severe allergic reactions (e.g., anaphylactic reactions, angioedema).
• Patients may not participate in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or the use of investigational devices with therapeutic intent within 30 days prior to randomization and while enrolled in this study. Caution is recommended when administering Sapu003 and concomitantly with known substrates, PgP inhibitors, inhibitors, and inducers of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4.
• Use of any strong inhibitors of cytochrome P450 (CYP) enzymes (e.g., fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP enzymes (e.g., barbiturates (phenobarbital), carbamazepine, phenytoin and rifampin), in the previous 14 days before randomization until the last blood draw in the study.
• Acute active infection requiring antibiotics, antiviral agents, or antifungal agents within 14 days prior to randomization
• Pregnant or lactating women.