This trial is an open-label, multi-center clinical study consisting of two periods: Phase Ⅰ and Phase Ⅱ. Phase I is a dose escalation study to determine MTD (maximum tolerated dose) and/or RP2D. Phase II is an expanded proof of concept (POC) study to evaluate the safety and efficacy of APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy for MIBC as measured by pCR.~Phase Ⅰ and Phase Ⅱ both are divided into 3 periods: screening period, neoadjuvant therapy and follow-up period:~The screening period is up to 4 weeks before the first doses of study treatments.~During the neoadjuvant therapy, each patient will receive the combined treatment of tislelizumab and APL-1202 or tislelizumab alone, every 21 days as a dosing cycle for a total of 3 cycles of treatment prior to radical cystectomy.~The follow-up period includes a safety follow-up at 4 weeks after radical cystectomy.~Phase Ⅰ: Dose-Escalation The dose escalation phase will assess the safety, tolerability, and pharmacokinetics of APL-1202 in combination with tislelizumab in MIBC patients. Results from this period will determine the RP2D of APL-1202 in combination with tislelizumab as neoadjuvant therapy for MIBC.~Patients enrolled in this phase must meet the following criteria: those with newly diagnosed MIBC for whom RC is planned, and who are cisplatin ineligible or refuse to receive cisplatin based neoadjuvant chemotherapy, and with calculated CrCl ≥ 50 mL/min (by Cockcroft-Gault equation).~A standard 3+3 dose-escalation design will be used. The dose of APL-1202 will start at 375 mg (125 mg, TID) and increase sequentially to 750 mg (250 mg, TID) and 1,125 mg (375 mg, TID). For more information on the dose escalation design, please see the Dose Escalation Criteria section.~Table 1: Dose-Escalation plan~Dose Level Tislelizumab APL-1202 Patients (n)~200 mg, IV, Q3w 125 mg, PO, TID ≥ 3~200 mg, IV, Q3w 250 mg, PO, TID ≥ 3~200 mg, IV, Q3w 375 mg, PO, TID ≥ 3 Patients will be assigned to one of three APL-1202 dose levels. Each patient will receive 3 cycles of treatment prior to RC and each cycle is 3 weeks. On day 1 of each cycle, a single dose of 200 mg tislelizumab will be administered intravenously and APL-1202 will be administered orally TID daily for 3 weeks. If the dose level 1 is determined to be safe and tolerable, 3 patients will be enrolled to Dose Level 2 and will receive their treatments in 3-week treatment cycles and safety will be assessed. This process is repeated one more time for the Dose Level 3.~The DLT observation window for any dose level will be treatment cycle 1 (1-21 days).~Patients who do not complete the DLT observation period (cycle 1) will be replaced unless the discontinuation of treatment is DLT-related.~DLT assessment will be performed during the first cycle (1-21 days) of study treatments. An evaluable patient is defined as a patient who has received at least 75% of planned APL-1202 doses during the first cycle of treatment and completed all the safety evaluations required for the first cycle, or any patient who has DLT during the first cycle. If a patient receives less than 75% of planned APL-1202 doses during the first cycle or withdraws from the study due to reasons other than DLT, the patient will be replaced.~There will be no intra-patient dose escalation. A patient will receive treatments of cycle 2 and cycle 3 or until unacceptable toxicity, disease progression, or discontinuation for any other reason.~Phase Ⅱ: Proof of Concept (POC) The primary objective of this phase is to evaluate the safety and efficacy of APL-1202 in combination with tislelizumab compared to tislelizumab alone as neoadjuvant therapy for MIBC as measured by pathologic complete response (pCR).~Patients enrolled in this phase must meet the following criteria: those with newly diagnosed MIBC for whom RC is planned, and who are cisplatin ineligible or refuse to receive cisplatin based neoadjuvant chemotherapy.~As shown in Figure 1 below, eligible patients will be randomly assigned to group 1 or group 2, with PD-L1expression level as a stratification factor. For those assigned to group 1, each patient will receive 3 cycles of treatment prior to RC and each cycle is 3 weeks. On day 1 of each cycle, a single dose of 200 mg tislelizumab will be administered intravenously. APL-1202 will be administered orally TID daily for 3 weeks at the RP2D defined from Phase I. For patients assigned to group 2, each patient will receive 3 cycles of treatments with a single dose of 200 mg tislelizumab administered on day 1 of each cycle, followed by RC. A patient will stay on treatment until completion of planned treatments, unacceptable toxicity, disease progression, or discontinuation for any other reason.~In this period, patients with renal function with calculated CrCl ≥ 30 mL/min (by Cockcroft-Gault equation) will be recruited. if patients with CrCl ≥ 50 mL/min, start dose of APL-1202 is recommended to be RP2D defined from Phase I; for patients with CrCl 30-50 mL/min, the dose of APL-1202 is recommended to be reduced by 1 dose level from RP2D defined from Phase I (from 1125 mg/day to 750 mg/day, or from 750 mg/day to 375 mg/day).
This trial is designed to evaluate the safety, efficacy, and biomarker response of APL-1202 in combination with tislelizumab as neoadjuvant therapy for patients with MIBC who are cisplatin ineligible or refuse cisplatin-based chemotherapy.