To determine the efficacy of oral APL-1202 administered consecutively for 12 weeks in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy based on the recurrence-free rate (RFR) at 12 months after APL-1202 treatment.
This trial was a single-arm, open-label, multi-center clinical study consisting of two periods: the dose-escalation and treatment period, and the follow-up and maintenance period. Dose-Escalation and Treatment Period APL-1202 was orally administered TID daily and continuously for 12 weeks. APL-1202 dose was increased from daily 300, 450, 600 to 750mg or maximum tolerated dose (MTD). A modified 3+3 design was employed: The dose was started at 300 mg and increased to 450 mg, 600 mg and 750 mg if there was no dose-limiting toxicity (DLT) in 3 subjects after 4-week consecutive administration of APL-1202. When the dose-escalation study was in progress, the doses for any newly enrolled subjects would be the starting dose or the highest dose confirmed with no DLT by the dose-escalation cohort at the time of enrollment. When the MTD or the 750 mg daily dose was attained as a safe dose, the dose for all subjects in the study or subsequently enrolled subjects would be MTD or 750 mg/day. Follow-up and Maintenance Period APL-1202 was orally administered at the highest safe dose proven by the dose-escalation cohort, continuously for 3 months; This period was 12 months. To fit the 3-month cystoscopy follow-up schedule, the maintenance therapy, starting from 3-month off, was given continuously every other 3 months, resulting in 6 months of dosing in total. APL-1202 daily administration schedule: The first dose: within 30 minutes after breakfast; The second dose: within 30 minutes after lunch, and there should be a 4-hour interval between the first and second doses; The third dose: taken with a light snack at night before going to bed.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
41
A modified 3+3 design was employed: The dose was started at 300 mg and increased to 450 mg, 600 mg and 750 mg if there was no dose-limiting toxicity (DLT) in 3 subjects after 4-week consecutive administration of APL-1202. When the dose-escalation study was in progress, the doses for any newly enrolled subjects would be the starting dose or the highest dose confirmed with no DLT by the dose-escalation cohort at the time of enrollment. When the MTD or the 750 mg daily dose was attained as a safe dose, the dose for all subjects in the study or subsequently enrolled subjects would be MTD or 750 mg/day.
Recurrence-free rate (RFR) at the end of 12-month follow-up in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy.
Recurrence-free rate (RFR) at the end of 12-month follow-up in subjects with high-risk NMIBC relapsed from intravesical chemo/BCG therapy.
Time frame: 12 months
Recurrence-free survival (RFS)
Recurrence-free survival (RFS)
Time frame: 12 months
Progression-free survival (PFS).
progression-free survival (PFS).
Time frame: 12 months
The safety and tolerability of APL-1202.
Post-medication safety assessment included laboratory parameters, physical examination, vital signs, performance status score, and AEs. Frequency and severity of AEs were rated in accordance with internationally agreed NCI CTC AE4.0.
Time frame: 12 months
Plasma Max Concentration - APL-1202 and its metabolites
PK measurement expressed as maximum plasma concentration for APL-1202 and metabolites
Time frame: Day 28
Plasma Steady state Concentration - APL-1202 and its metabolites
PK measurement expressed as Steady state Concentration for plasma APL-1202 and its metabolites
Time frame: Day 28
Plasma Area Under Curve - APL-1202 and its metabolites
PK measurement expressed as area under curve for plasma APL-1202 and its metabolites
Time frame: Day 28
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Urinary excreted amounts- APL-1202 and its metabolites
PK measurement expressed as Urinary excreted amounts for APL-1202 and its metabolites
Time frame: Day 28
Cumulative urinary excreted amounts- APL-1202 and its metabolites
PK measurement expressed as Cumulative Urinary excreted amounts for APL-1202 and its metabolites
Time frame: Day 28
Cumulative fraction of dose- APL-1202 and its metabolites
PK measurement expressed as Cumulative fraction of dose for APL-1202 and its metabolites
Time frame: Day 28
The SNV(single-nucleotide variant) patterns of bladder cancer related genes in pre- and post-treatment plasma ctDNA (circulating tumor DNA) through targeted amplicon sequencing
Blood ctDNA were extracted from the patients before APL-1202 treatment or after APL-1202 treatment; somatic SNV were detected by targeted amplicon sequencing. Evaluation of RFR (Recurrence-free rate), RFS (Recurrence-free survival), PFS (Progression-free survival) and baseline SNV will be performed using cox regression survival model.
Time frame: 12 months
The InDel (insertion-deletion) patterns of bladder cancer related genes in pre- and post-treatment plasma ctDNA (circulating tumor DNA) through targeted amplicon sequencing
Blood ctDNA were extracted from the patients before APL-1202 treatment or after APL-1202 treatment; somatic InDel were detected by targeted amplicon sequencing. Evaluation of RFR (Recurrence-free rate), RFS (Recurrence-free survival), PFS (Progression-free survival) and baseline InDel will be performed using cox regression survival model.
Time frame: 12 months