A Phase II Study to Evaluate the Efficacy and Safety of TLC388 in Advanced/Metastatic RCC Patients

A Phase II, open-label, single-arm, multi-center study to evaluate TLC388 monotherapy in patients with locally advanced and/or metastatic RCC. The study consisted of a Screening/Baseline Period, a Treatment Period and a post-treatment Follow-Up Period for PFS and OS.

Patients were to be recruited at two stages. Stage I recruited 15 evaluable patients, who had completed at least 2 cycles of treatment with one tumor assessment. If ≤ 5 patients did not develop PD at the end of cycle 6 per RECIST, no patients were to be recruited for Stage II and the study was to be closed. If > 5 patients did not develop PD at the end of cycle 6, a total of 40 evaluable patients (additional 25 evaluable patients for Stage II) were to be recruited thereafter.

Inclusion criteria

• Adult patients defined by age ≥ 18 years
• Histologically confirmed Renal cell carcinoma (RCC)
• Locally advanced or metastatic RCC. Locally advanced RCC: defined as a stage T3/T4 disease, not amenable to curative surgery or radiation therapy, with involvement of renal vein/vena cava/peripelvic and perirenal fat/adrenal gland, or invasion beyond Gerota's fascia. Metastatic RCC: equivalent to Stage IV RCC, according to American Joint Committee on Cancer (AJCC) staging
• Eastern Collaborative Oncology Group (ECOG) Performance Status of ≤ 2. But for the patient with failure of ≥ 2 prior target therapies, ECOG should be ≤ 1.
• Documented RCC disease with measurable or non-measurable lesion on imaging by RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) criteria
• Documented treatment failure of at least 1 prior target therapy (sorafenib, sunitinib pazopanib or other VEGF TKI, bevacizumab, temsirolimus, everolimus or other mTOR inhibitor) for advanced or metastatic RCC. If treatment-naïve, patients with poor prognosis features according to Memorial Sloan-Kettering Cancer Centre (MSKCC) risk criteria are acceptable
• Any acute or chronic adverse effects of prior therapy have resolved to <Grade 2 as determined by CTCAE v4.0 criteria
• Laboratory values at screening:

• Absolute neutrophil count ≥ 1,500 /mm3;
• Platelets ≥ 100,000 /mm3;
• Hemoglobin ≥ 9.0 g/dL;
• Total bilirubin ≤ 1.5 times the upper limit of normal;
• AST (SGOT) ≤ 2.5 times the upper limit of normal;
• ALT (SGPT) ≤ 2.5 times the upper limit of normal;
• Serum creatinine ≤ 2 times the upper limit of normal;

Exclusion criteria

• Pregnancy or lactation. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrolment. Male and female patients of childbearing potential must agree to use appropriate birth control (barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study, or the patient must be surgically sterile (with documentation in the patient's medical records)
• Receipt of any chemotherapy for RCC
• Had cardiac angioplasty or stenting event, myocardial infarction or unstable angina within 3 months of study entry
• Persistent QTc >450 ms for males, or >470 ms for females, according to Fridericia's correction
• Patients with Grade 3 or greater hyponatremia at screening
• History of Class III or IV congestive heart failure according to New York Heart Association (NYHA) classification
• History of another malignancy, except for non-basal-cell carcinoma of skin or carcinoma-in-situ of the uterine cervix, and not disease free ≥5 years
• History or presence of central nervous system (CNS) metastasis or leptomeningeal tumors as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam
• History of human immunodeficiency virus infection
• Presence of active, uncontrolled infection
• Radiotherapy received within 4 weeks prior to baseline
• Use of any investigational agents within 4 weeks of baseline
• Major surgery within 4 weeks prior to baseline
• Receipt of radiotherapy to >25 % of bone marrow
• Concomitant treatment with, or anticipated use of, pharmaceutical or herbal agents which are potent inhibitors or inducers of cytochrome P450 enzymes (Appendix D1), unless approved by the Sponsor
• Uncontrolled intercurrent illness that would jeopardize patient safety, or interfere with the objectives of the protocol, or limit patient compliance with study requirements, as determined by the Investigator