A Phase 3 Study to Evaluate the Safety and Efficacy of APL-1202 as a Single-agent Oral Treatment Versus Intravesical Instillation of Epirubicin Hydrochloride in naïve Intermediate-risk NMIBC Patients

A Multi-center, Randomized, Open-label, Parallel-controlled Phase 3 Clinical Trial to Evaluate the Clinical Safety and Efficacy of APL-1202 as a Single-agent Oral Treatment Versus Intravesical Instillation of Epirubicin Hydrochloride in naïve Intermediate-risk Non-muscle Invasive Bladder Cancer (NMIBC) Patients

A multi-center, randomized, open-label, parallel-controlled Phase Ⅲ clinical trial to evaluate the clinical safety and efficacy of APL-1202 as a single-agent oral treatment versus intravesical instillation of Epirubicin hydrochloride in naïve intermediate-risk non-muscle invasive bladder cancer (NMIBC) patients

A multi-center, randomized, open-label, placebo controlled Phase Ⅲ trial. The subjects must be histopathologically diagnosed, naïve intermediate-risk NMIBC patient. The screening period is 6 weeks prior to treatment.

The trial including 2 stages:

• First stages: The subjects are randomly assigned to receive APL-1202 single-agent oral treatment or intravesical instillation of Epirubicin hydrochloride at a ratio of 1:1. At this stage, an interim analysis will be performed after the first 100 subjects enrolled completing the 6-month visit (completing the second cystoscopy), and the Independent Data Monitoring Committee (IDMC) conducted a preliminary evaluation of the safety. If approved by the IDMC after the safety evaluation, the trial will proceed to the second stage. Before the result of the interim analysis are obtained, subjects receiving APL-1202 will continue to be given continuous administration if they have completed the 6-month visit (V4). After the interim analysis, if the safety of continuous administration is as expected, subjects receiving APL-1202 will continue to do the same, otherwise it will be adjusted to the administration of APL-1202 at every 3-month interval which is proven to be safe and tolerable.

• Second stage: After the interim analysis of the first stage, the subjects of the second stage will be enrolled, and the subjects were randomly assigned to receive APL-1202 single-agent oral treatment or intravesical instillation of Epirubicin hydrochloride at a ratio of 1:1. For treatment, according to the results of the interim analysis, if the safety of continuous administration reaches the expected level, subjects receiving APL-1202 will continue to do the same, otherwise it will be adjusted to the administration of APL-1202 at every 3-month interval which is proven to be safe and tolerable.

In this trial, the APL-1202 dosing regimen will continue until subjects exit the trial early for any reason, complete 24 months' treatment or the trial is terminated early.

Cystoscopy will be performed every 3 months in the enrolled subjects. If there is no recurrence in the enrolled subject during the treatment period (2 years after enrollment), cystoscopy will be performed every 6 months during the follow-up period until recurrence or the end of the clinical trial.

Safety assessment will be performed every 3 months during the treatment period.

Inclusion Criteria:

All patients must meet all the following criteria:

• Must be informed of the investigational nature of this study and must provide written informed consent
• Age ≥18 years, male or female
• Non-muscle invasive transitional cell carcinoma of the bladder is histologically confirmed by Independent Pathology Review Committee (IPRC). Diagnosis and classification of intermediate-risk NMIBC is according to 2014 CUA Guideline of Diagnosis and Treatment of Urological Diseases in China:

Low-risk: Primary, solitary, TaGl (PUNLMP, low-grade urothelial carcinoma), <3cm, no CIS. (Note: the above conditions must be met at the same time as a low-risk NMIBC) Intermediate-risk: All tumours not defined in the two adjacent categories (between the category of low and high risk) High-risk: Any of the following: ① T1 tumour; ②G3(high-grade urothelial carcinoma) tumour;③carcinoma in situ (CIS); ④ Multiple, recurrent and large (> 3 cm) TaG1G2(low-grade urothelial carcinoma) tumours (all features must be present)

• No visible tumor after transurethral resection of bladder tumor (TURBT) on tumor lesion. Some requirements about Re-TURBT are as follows: It is recommended to conduct the secondary TURBT under following situations: incomplete first TURBT; no muscle tissue found in the first TURBT specimen, except Ta G1 (low grade) tumor and CIS only.

The secondary TURBT is recommended 2-6 weeks, but better at 4 weeks, after the first TURBT.

For subjects undergoing secondary TURBT, they will be enrolled after the second TURBT

• Subjects who never received intravesical instillation (including BCG or intravesical chemotherapy) prior to enrollment, except single, immediate, post-operative intravesical chemotherapy.
• Willing to provide pathological tissue specimen for assessment
• ECOG PS ≤ 1
• Patients, who have not received blood transfusion or colony-stimulating factor treatment within 14 days before the examination, must have normal organ and marrow function within 42 days of study entry (according to normal range in clinical site).

Absolute neutrophil count >1.5×109/L Platelets > 100 ×109/L Hemoglobin > 9.0 g/dL Alkaline phosphatase < 2.5 ULN GFR (Cockcroft-Gault formula calculated) ≥ 50 mL/min Total bilirubin, alanine aminotransferase or aspartate aminotransferase< 1.5 ULN INR <1.5, except for subjects receiving anticoagulation therapy

• Female should be either surgically sterilized or menopause or agree to use effective contraceptive measures during treatment. Women of reproductive age must have a negative result of pregnancy test during the screening period (pregnancy test will be not required if one of the following situations exists: the subject has undergone sterilization such as hysterectomy and/or bilateral oophorectomy, has no menstruation for 12 months and been diagnosed as menopause based on factors such as age). However, pregnancy tests are required for patients with bilateral fallopian tube ligation.
• Male subjects should be either surgically sterilized or agreed to use effective contraceptive measures. From signing the informed consent, subjects must take continuous measures until 3 months after the end of the treatment of trial. The definition of effective contraceptive measures will be based on the principal investigator(PI) or appointed delegate.
• Expected life expectancy is more than 48 months

Exclusion Criteria:

The presence of any of the following will exclude a patient from study enrollment:

• Low-risk: Primary, solitary, TaGl (PUNLMP, low-grade urothelial carcinoma), <3cm, no CIS. (PS: the above conditions must be met at the same time as a low-risk NMIBC)
• High-risk: Any of the following: ① T1 tumour; ②G3(high-grade urothelial carcinoma) tumour;③carcinoma in situ (CIS); ④ Multiple, recurrent and large (> 3 cm) TaG1G2(low-grade urothelial carcinoma) tumours (all features must be present)
• Tumors of T2 stage or more serious
• The histological types are mainly non-urothelial carcinomas such as squamous cell carcinoma and adenocarcinoma
• Urothelial carcinoma outside the bladder (renal pelvis, ureter or urethra)
• Received intravesical therapy in last TURBT/cystoscopy prior to treatment period, but not including immediate intravesical therapy once (the subjects who received the immediate intravesical therapy need to be recorded in e-CRF)
• Received surgery (not includes TURBT/cystoscopy), radiation therapy, or systemic therapy within 6 weeks before enrollment
• Malignancies within 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in-situ' of the cervix
• Grade 3 (according to the NCI CTCAE 5.0) hemorrhage in any part of body within 6 weeks before starting the treatment of trial
• Any of the following within 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
• Hypertension that cannot be controlled by medications (systolic blood pressure≥140 mmHg and/or diastolic blood pressure≥90mmHg)
• Uncontrolled active infections before starting the treatment of trial, such as acute pneumonia, active hepatitis B, etc.
• Dysphagia or known drug absorption disorders
• Anuria
• One week prior to enrollment, having gross hematuria
• Active duodenal ulcers, ulcerative colitis and other gastrointestinal diseases or other conditions that the investigator may determine to cause gastrointestinal bleeding or perforation
• The risk of participation or administration may increase, judged by investigator, or other severe acute or chronic medical conditions may interfere with the interpretation and judgment of results
• or optic nerve disorders
• Subjects have optic nerve disorders and cataracts, or other related medical history
• Pregnancy or breastfeeding. Female patients with reproductive potential have a positive pregnancy test prior to enrollment
• Psychological or mental abnormality, subjects are estimated to have insufficient adherence to this clinical study
• Four weeks prior to enrollment, participate in other clinical trials
• Patients who had previously received anthracycline for systemic chemotherapy