Safety and Efficacy of APL-1202 in Combination With Epirubicin Hydrochloride Versus Epirubicin Hydrochloride Alone in Intermediate and High-risk Chemo-refractory Non-muscle Invasive Bladder Cancer (NMIBC) Patients (ACCRUE)

A Multi-center, Randomized, Double-blind, Placebo-controlled Phase Ⅲ Clinical Trial to Evaluate the Clinical Safety and Efficacy of APL-1202 in Combination With Epirubicin Hydrochloride Versus Epirubicin Hydrochloride Alone in Intermediate and High-risk Chemo-refractory Non-muscle Invasive Bladder Cancer (NMIBC) Patients

To evaluate the clinical efficacy (median event-free survival) of APL-1202 in combination with Epirubicin hydrochloride versus Epirubicin hydrochloride alone in intermediate and high-risk chemo-refractory non-muscle invasive bladder cancer (NMIBC) patients

Study Overview

• Status: Active, not recruiting
• Conditions: Non-muscle Invasive Bladder Cancer
• Intervention / Treatment: Drug: APL-1202 in combination with Epirubicin; Drug: Placebo in combination with Epirubicin

Detailed Description

A multi-center, randomized, double-blind, placebo controlled Phase Ⅲ trial; including 3 stages: screening period, treatment period, and follow-up period.

• Screening period: 6 weeks prior to treatment
• Treatment period:
• Induction period: APL-1202 is administered for 12 consecutive weeks
• Maintenance period: after 12-week drug free period, APL-1202 is administered for another12 consecutive weeks as maintenance treatment
• Follow up period: APL-1202 is administered at every 3-month interval if no events occurred in the treatment period and until the occurrence of events or the end of the entire clinical trial Intravesical Epirubicin hydrochloride will be administered once weekly for consecutive 6-8 weeks in the induction period, followed by once monthly in the maintenance period until end of 12 months

• Study Type: Interventional
• Enrollment (Actual): 359
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China
      • Fudan University Shanghai Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must be informed of the investigational nature of this study and must provide written informed consent
• Age ≥18 years, male or female
• Must have clinically and histologically confirmed recurrent intermediate and high-risk non-muscle invasive transitional cell carcinoma of the bladder after treatment with intravesical chemotherapy. EORTC risk score (according to EUA "NMIBC Guideline" 2015 version) must be ≥ 5: Papilloma alone (or with Cis) or Cis alone No visible tumor after TURBT on tumor lesion
• Medical history of intravesical chemotherapy Subjects who received intravesical chemotherapy prior to enrollment, but didn't receive BCG or other intravesical therapy with immune drugs Subjected who are refractory to the recommended intravesical chemotherapy drugs pirarubicin, epirubicin, doxorubicin, hydroxy camptothecin, mitomycin, or gemcitabine (according to "Guideline of Diagnosis and Treatment of Urological Diseases in China", 2014 version)
• Re-TURBT:

For subjects undergoing secondary TURBT, EORTC risk score must be ≥ 5, which can be assessed based on the results of any TURBTs. The other results will be based on first TURBT For subjects undergoing secondary TURBT, the enrollment time will start from the second TURBT 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; T1 tumor; G3 (high grade) tumor (except CIS) The secondary TURBT is recommended 2-6 weeks, but better at 4 weeks, after the first TURBT

• Willing to provide biopsy specimen for assessment
• ECOG PS ≤ 1, and did not deteriorate in 7 days
• Patients must have normal organ and marrow function within 42 days of study entry (according to normal range in clinical site) Absolute neutrophil count >1.0×109/L Platelets > 100 ×109/L Hemoglobin > 9.0 g/dl Alkaline phosphatase < 2.5 ULN (<10 X ULN in presence of bone metastasis) GFR (Cockcroft-Gault formula calculated) ≥ 50 ml/min INR <1.5, except for subjects receiving warfarin therapy
• Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of APL-1202 will be determined following review of their case by the Principal Investigator
• Female should be either surgically sterilized or menopause or agree to use effective contraceptive measures during treatment
• Male subjects must be surgically sterilized or agreed to use effective contraceptive measures. Subjects must continue to take contraceptive measures within 3 months of the end of the study treatment. The definition of effective contraceptive measures will be based on the Principal Investigator or appointed delegate;
• Expected life expectancy is more than 30 months

Exclusion Criteria:

• TBIL, ALT or AST >1.5 x normal range (according to normal range in clinical sites)
• Urothelial cell carcinoma in upper urethra or ureter
• Received intravesical therapy in last TURBT/cystoscopy prior to enrollment 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
• NCI CTCAE grade 3 hemorrhage within 6 weeks of starting study treatment
• 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 such as acute pneumonia, active hepatitis B, etc.
• Dysphagia or known drug absorption disorders
• Anuria
• One week prior to enrollment, having hematuria
• Active duodenal ulcers, ulcerative colitis and other gastrointestinal diseases or other conditions that the investigator may determine to cause gastrointestinal bleeding or perforation
• Subjects that may increase the risk associated with study participation or study drug administration, judged by investigator, or other severe acute or chronic medical condition or optic nerve disorders may interfere with the interpretation and judgment of study results
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo in combination with Epirubicin; Induction period: placebo is administered for 12 consecutive weeks; Maintenance period: after 12-week drug free period, placebo is administered for another12 consecutive weeks as maintenance treatment; Follow up period: APL-1202 is administered at every 3-month interval if no events occurred in the treatment period and until the occurrence of events or the end of the entire clinical trial Intravesical Epirubicin hydrochloride will be administered once weekly for consecutive 6-8 weeks in the induction period, followed by once monthly in the maintenance period until end of 12 months
Experimental: APL-1202 treatment	Drug: APL-1202 in combination with Epirubicin; Induction period: APL-1202 is administered for 12 consecutive weeks; Maintenance period: after 12-week drug free period, APL-1202 is administered for another12 consecutive weeks as maintenance treatment; Follow up period: APL-1202 is administered at every 3-month interval if no events occurred in the treatment period and until the occurrence of events or the end of the entire clinical trial Intravesical Epirubicin hydrochloride will be administered once weekly for consecutive 6-8 weeks in the induction period, followed by once monthly in the maintenance period until end of 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	"Event"is defined as: pathologically confirmed recurrence, progression, or death resulting from bladder cancer	Up to 30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent-free rate	Recurrent-free rate	24 months
Progression-free rate	Progression-free rate	24 months
Clinical benefit rate at 12,18, 24 months after enrollment (clinical benefits are defined as the pathological improvement of the recurrence, no high-risk recurrence, progression-free recurrence, no radical therapy and no death)	Clinical benefit rate at 12,18, 24 months after enrollment (clinical benefits are defined as the pathological improvement of the recurrence, no high-risk recurrence, progression-free recurrence, no radical therapy and no death)	24 months
Recurrence-free survival	Recurrence-free survival	Up to 30 months
Progression-free survival	Progression-free survival	Up to 30 months
Total survival	Total survival	Up to 30 months

Collaborators and Investigators

• Sponsor: Jiangsu Yahong Meditech Co., Ltd aka Asieris
• Investigators: Principal Investigator: Dingwei Ye, MD,PhD, Fudan University; Principal Investigator: Hanzhong Li, MD,PhD, Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2017
• Primary Completion (Anticipated): May 30, 2022
• Study Completion (Anticipated): May 30, 2022

Study Registration Dates

• First Submitted: July 23, 2020
• First Submitted That Met QC Criteria: July 26, 2020
• First Posted (Actual): July 29, 2020

Study Record Updates

• Last Update Posted (Actual): February 22, 2022
• Last Update Submitted That Met QC Criteria: February 21, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Epirubicin
• Other Study ID Numbers: YHCT-NIT-R1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No