An Open-label, Randomized Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of the Combination Therapy of SLC-3010 and Axitinib Compared to Axitinib Monotherapy as a Second-line Treatment for Locally Advanced or Metastatic Clear Cell Renal Cell Carcinoma

"Part 1 (Safety Run-in): The safety run-in phase consists of a single-arm cohort of SLC-3010 in combination with axitinib and will be conducted to determine the optimal dose of the SLC-3010 combination regimen before proceeding to phase 2. At each dose level of SLC-3010, 6 patients will be enrolled and the safety and tolerability will be assessed based on defined DLT criteria. The dose will be escalated or de-escalated stepwise based on the dose level identified from the SLC-3010-001 monotherapy dose-escalation cohort.

In the safety run-in phase, the first patient enrolled at each dose level will be observed for safety for 48 hours (monitoring period) after administration. If the patient tolerates the treatment appropriately during this period, 5 additional patients may be enrolled.

The starting dose in the safety run-in will be one dose level below the maximum tolerated dose (MTD) of SLC-3010 monotherapy verified in the SLC-3010-001 study(0.15mg/kg).

The DLT observation period will be 21 days. If 1 or none of the 6 patients at the starting dose level experiences a DLT, the dose will be escalated to the next higher level. If DLTs are observed in 1 or fewer patients at the higher dose level, the dose will be escalated to the next level. If 2 out of the 6 patients at the starting dose level experience a DLT, the dose will be de-escalated to the next lower level. Upon completion of the safety run-in, the Data and Safety Monitoring Board (DSMB) will determine the MTD of SLC-3010 in combination with axitinib. This determination will consider safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data.

Part 2 (Phase 2):

In Part 2, the anti-tumor activity and safety of SLC-3010 in combination with axitinib will be evaluated. Patients in Part 2 will receive treatment at the MTD identified during the safety run-in. A total of 60 patients (30 patients per group) will be enrolled and randomized after stratification based on prior treatment history with tyrosine kinase inhibitors (TKIs) including immune-oncology (IO) therapy including immune-oncology (IO) therapy (i.e., IO + IO versus IO + TKI).

SLC-3010 will be administered via intravenous (IV) infusion at the defined dose on Day 1 of each 21-day cycle, and the infusion rate will be 100 mL/hour throughout each cycle. If the patient tolerates the first cycle, SLC-3010 may be administered over 30 minutes in subsequent cycles (100 mL/30 min).

Axitinib is a small molecule tyrosine kinase inhibitor. It will be administered orally at 5 mg twice daily regardless of the timing of SLC-3010 administration.

Inclusion criteria

• Histologically or cytologically confirmed diagnosis of locally advanced or metastatic ccRCC.

• Part 1 (Safety Run-in): At least one first-line treatment of standard of care in the recurrent/metastatic setting.
• Part 2 (Phase 2): Anti-PD-1 (Programmed Cell Death Protein 1) or anti-PD-L1 (Programmed Cell Death-Ligand 1) monotherapy or combination therapy as first-line treatment in the recurrent/metastatic setting.
• At least one measurable lesion as defined by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1.
• Male or female patients aged ≥ 19 years at the date on which the informed consent is signed.
• Ability and willingness to provide written informed consent and to comply with all study procedures.
• Estimated life expectancy of ≥ 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ functions as defined below. System organ class Laboratory test results

• Hematology

: Absolute neutrophil count (ANC) ≥ 1500 cells/μL without the support of granulocyte colony-stimulating factor (G-CSF) within 2 weeks prior to the first dose of the study intervention.

Platelet count ≥ 100,000/μL without the support of transfusion within 2 weeks prior to screening laboratory sample collection.

Hemoglobin ≥ 9 g/dL without the support of transfusion within 2 weeks prior to screening laboratory sample collection.

• Coagulation

:International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × the upper limit of normal (ULN). If the patient is receiving anticoagulant therapy, PT shall be within the therapeutic range for the intended use of anticoagulants.

• Kidney

:Estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. ≥ 40 mL/min/1.73 m2

• Liver :Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients with Gilbert's syndrome), or if total bilirubin is > 1.5 × ULN, direct bilirubin ≤ ULN.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with documented liver metastases).

Albumin ≥ 2.8 g/dL

• If there were any clinically significant toxicities from prior therapies, they shall have resolved to Grade 0 or Grade 1 according to the NCI CTCAE v5.0 (Alopecia and ≤ Grade 2 endocrine-related adverse events related to prior immunotherapy (e.g., immune checkpoint inhibitors) that require medical treatment or hormone replacement therapy are considered acceptable for study participation.).
• Male and female patients of childbearing potential shall agree to use existing, highly effective contraception methods with the failure rate of <1% (Appendix 1) during the treatment period and for 3 months after the last administration of the study intervention. Acceptable methods shall include barrier methods such as spermicide condoms or diaphragms. Women of childbearing potential (WOCBP) are defined as females who have experienced menarche and are not postmenopausal (including amenorrhea for at least 2 years without hormone therapy or surgical sterilization).
• WOCBP shall have a documented negative serum or urine pregnancy test at screening, performed within 3 days prior to the first administration of the study intervention. For non-childbearing females, one of the following shall be documented:

• Postmenopausal status, defined as the absence of regular menstruation for at least 12 consecutive months with a documented serum follicle-stimulating hormone (FSH) level within the laboratory reference range for postmenopausal women, or
• Documented history of hysterectomy or bilateral oophorectomy, or
• Medically confirmed ovarian failure.

Exclusion criteria

• History of malignancy or active malignancy other than the target disease in this study. Exceptions are as follows:

• Malignancies that have been treated with curative intent and have not recurred within the recent 2 years.
• Completely resected basal cell carcinoma or squamous cell carcinoma of the skin.
• Any type of completely resected carcinoma in situ.
• Known brain metastases or epidural conditions. However, patients who have been sufficiently treated with radiotherapy and/or surgery (including radiosurgery) and have been stable for at least 4 weeks prior to the first administration of the study intervention can be enrolled. Note: Patients with an incidental finding of a single lesion <1 cm may be eligible if deemed not to require treatment at the discretion of the investigator. Eligible patients shall be neurologically asymptomatic and shall not have received corticosteroid therapy for at least 2 weeks prior to the first administration of the study intervention.
• Diagnosis of immunodeficiency or current use of chronic systemic corticosteroids or other immunosuppressive therapy within 7 days prior to the first administration of the study intervention. Topical (< Grade III), inhaled corticosteroids, or intra-articular corticosteroids, topical creams/lotions, mouthwashes containing corticosteroids, or mineralocorticoids (e.g., fludrocortisone) are allowed.

Note: Chronic use of ≤ 10 mg/day of prednisone or equivalent may be allowed after discussion and approval by the lead institution.

• Active autoimmune disease that has required systemic treatment (e.g., disease controllers, corticosteroids, or immunosuppressive drugs) within the recent 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal insufficiency or hypopituitarism) is not considered a form of systemic treatment.
• Known infection with Human Immunodeficiency Virus-1 (HIV-1) or HIV-2. Known active hepatitis B virus infection (i.e., HBsAg positive) or hepatitis C virus infection (e.g., [qualitatively] detectable HCV RNA). Patients with a negative HCV RNA test after a positive HCV antibody test and no ongoing anti-HCV therapy.
• Active infection requiring systemic therapy.
• Significant cardiovascular diseases, including but not limited to: Stable arrhythmias medically controlled with ongoing medication are allowed.

• QT interval (Interval from the start of the Q wave to the end of the T wave of the ECG) corrected for heart rate using Fridericia's formula (QTcF) > 480 msec at screening
• Myocardial infarction, acute coronary syndrome, or history of coronary angioplasty/stenting/bypass grafting within the recent 6 months.
• Congestive heart failure (CHF) classified as New York Heart Association (NYHA) Class II-IV, or a history of NYHA Class III or IV CHF.
• Patients with significant respiratory symptoms, known or suspected serious or severe pulmonary conditions at screening, or requiring supplemental oxygen.
• Any form of systemic anticancer therapy (including investigational therapy) within 3 weeks prior to the first administration of the study intervention, or within 5 half-lives of the drug if known, whichever is shorter.
• Participation in an interventional clinical trial involving an investigational drug or device within 3 weeks prior to the first administration of the study intervention in this clinical trial. Patients who are participating in follow-up may be enrolled if more than 3 weeks have passed since the last administration.
• Radiotherapy within 2 weeks prior to the first administration of the study intervention. Patients with ongoing clinically related complications from prior radiotherapy are not eligible.
• Major surgery within 2 weeks prior to administration of the study intervention. Patients shall have sufficiently recovered from any toxicity and/or complications at the discretion of the investigator.
• Live vaccine administration within 4 weeks prior to the first administration of the study intervention. Administration of non-live COVID-19 vaccines within 7 days prior to the DLT assessment is contraindicated, as vaccine-related toxicity may interfere with safety assessments.
• Prior therapy using IL-2 (interleukin-2)-based drugs.
• History of prior axitinib treatment.
• Inability to swallow oral drugs or presence of gastrointestinal disorders that may affect absorption (e.g., gastrectomy, partial bowel obstruction, or malabsorption syndrome).
• Current administration of potent CYP3A4 inducers (e.g., mitotane, phenytoin, rifampin, carbamazepine, or St. John's Wort) that cannot be discontinued during the study.
• Current administration of potent CYP3A4 inhibitors (e.g., boceprevir, cobicistat, itraconazole, ketoconazole, clarithromycin, idelalisib, nefazodone, nelfinavir, and ritonavir co-administered with protease inhibitors) that cannot be discontinued during the study.
• Medically significant bleeding within 3 months prior to randomization. Tumor invasion/infiltration of major blood vessels shall be evaluated, and the potential risk of severe hemorrhage due to tumor shrinkage or necrosis will be considered as part of the exclusion assessment.
• Ongoing concomitant treatment at a therapeutic dose with anticoagulants such as heparin, thrombin, or factor Xa inhibitors, or with antiplatelet agents (e.g., clopidogrel).

• Low-dose aspirin (≤ 100 mg/day), prophylactic low molecular weight heparin (LMWH), and prophylactic factor Xa inhibitors are acceptable.
• Anticoagulation therapy with LMWH at a therapeutic dose is allowed in participants who have no radiologic evidence of uncontrolled brain metastases, have been on a stable dose of LMWH for at least 2 weeks prior to randomization, and have no history of thromboembolic complications or complications from anticoagulation therapy.
• Presence of the following clinically significant diseases:

• Unhealed serious active wounds, ulcers, or fractures
• Requirement for hemodialysis or peritoneal dialysis.
• History of solid organ transplantation.
• Ascites with symptoms requiring medical intervention.
• Known hypersensitivity to any component of the study intervention (SLC-3010 or axitinib), or their analogs.
• Any condition, therapy, laboratory abnormality, or other circumstance (medical history or current evidence) that may expose the patient to risk by participating in the clinical trial, cause confusion in study results, or interfere with the patient's participation throughout the study.
• Psychiatric or substance abuse disorders known to interfere with compliance with study requirements.
• For female patients only: Pregnant or breastfeeding.