A Phase I/II Clinical Study Evaluating the Safety, Efficacy, Tolerability, and Pharmacokinetics of HS-10566 in Patients With High-risk Non-muscle-invasive Bladder Cancer Who Are Ineligible for or Refuse Radical Cystectomy
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- Jiangsu Hansoh Pharmaceutical Co., Ltd.
- Enrollment
- 180
- Locations
- 2
- Primary Endpoint
- Phase I: RP2D
Overview
Brief Summary
This is a multicenter, open-label, Phase I/II clinical study evaluating the safety, efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profiles of HS-10566 in patients with high-risk non-muscle-invasive bladder cancer who are ineligible for or refuse radical cystectomy. The study comprises two distinct phases: a dose exploration phase and a proof-of-concept phase.
Detailed Description
The study will commence with a dose exploration phase employing a safety lead-in approach. Treatment cycles are 28 days in duration, with investigational product administration continuing for 2 years or until disease progression or fulfillment of other treatment discontinuation criteria. Each dose level will enroll 6 participants for dose-limiting toxicity (DLT) assessment to evaluate the tolerability, safety, and PK/PD profiles of HS-10566. The Safety Review Committee (SRC) will determine subsequent dose levels for exploration via joint review.
Following identification of safe dose levels in the exploration phase, one dose cohort will advance to the proof-of-concept phase, with each cohort enrolling up to 50 participants to further assess therapeutic efficacy and safety.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Men or women aged greater than or equal to (≥) 18 years.
- •Signed informed consent form.
- •Histologically confirmed non-muscle-invasive bladder urothelial carcinoma (i.e., transitional cell carcinoma). Mixed tumor types predominantly consisting of urothelial carcinoma are eligible. Patients diagnosed with neuroendocrine, micropapillary, signet-ring cell, plasmacytoid, or sarcomatoid features are excluded.
- •Patients with non-muscle-invasive bladder cancer (NMIBC) who have undergone prior transurethral resection of bladder tumor (TURBT) and who refuse or are ineligible for radical cystectomy, and meet one of the following two populations:
- •Patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) who are unresponsive to Bacillus Calmette-Guérin (BCG) therapy after prior TURBT, and who refuse or are ineligible for radical cystectomy. BCG unresponsive is defined as occurrence of any one of the following in NMIBC patients after adequate BCG therapy (at least 5 full dose inductions and at least 2 maintenance instillations of BCG):
- •Persistent or recurrent CIS within 12 months after adequate BCG therapy, with or without recurrence of high-grade Ta or T1 tumors;
- •Recurrence of high-grade Ta/T1 tumors within 6 months after adequate BCG therapy (disease-free);
- •Recurrence of high-grade tumors at the first assessment during maintenance therapy after adequate BCG induction.
- •Patients who have not received BCG therapy after prior TURBT, including the following three scenarios:
- •NMIBC patients who failed intravesical chemotherapy, and who refuse or are ineligible for repeat postoperative intravesical chemotherapy or BCG instillation by the investigator.
Exclusion Criteria
- •Histopathologically confirmed muscle invasive (pathologic T stage ≥ T2), locally advanced, unresectable, or metastatic urothelial carcinoma.
- •Urothelial carcinoma outside the bladder (e.g., urethra, ureter, renal pelvis) unless radically resected with no disease recurrence for \> 2 years.
- •History of other primary solid tumors, except:
- •Radically treated solid tumor with no activity for ≥5 years before enrollment and low recurrence risk;
- •adequately treated non-melanoma skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma) or lentigo maligna with no evidence of recurrence;
- •adequately treated carcinoma in situ (e.g., cervical, ductal carcinoma in situ of breast) with no evidence of recurrence.
- •Has received or is receiving any of the following treatments:
- •Regular intravesical chemotherapy (gemcitabine, pirarubicin, mitomycin, etc.) or BCG instillation intolerance following TURBT/bladder biopsy before enrollment.
- •Pelvic radiotherapy within 4 weeks prior to first study treatment. Patients with last radiotherapy \>4 weeks prior and no confirmed radiation cystitis may be enrolled.
- •Major surgery (TURBT is not considered major surgery) within 4 weeks before first study treatment, or incomplete recovery from postoperative complications.
Arms & Interventions
Arm 1:Bacillus Calmette-Guerin (BCG)-unresponsive participants with carcinoma in situ.
HS-10566 is placed into the bladder through a urinary placement catheter in participants with CIS, with or without papillary disease, on Day 1 and will be dosed Q4W for up to the first 24 weeks (6 months), then every 12 weeks through Week 96 (Year 2).
Intervention: HS-10566 (Drug)
Arm 2: BCG-unresponsive participants with high-risk papillary-only disease
HS-10566 is placed into the bladder through a urinary placement catheter in participants with papillary disease only, on Day 1 and will be dosed Q4W for up to the first 24 weeks (6 months), then every 12 weeks through Week 96 (Year 2).
Intervention: HS-10566 (Drug)
Arm 3: BCG-naïve participants with high-risk disease
HS-10566 is placed into the bladder through a urinary placement catheter in participants with BCG-naïve high-risk disease, on Day 1 and will be dosed Q4W for up to the first 24 weeks (6 months), then every 12 weeks through Week 96 (Year 2).
Intervention: HS-10566 (Drug)
Outcomes
Primary Outcomes
Phase I: RP2D
Time Frame: Up to 5 months
Phase II Arm 1: overall complete response (CR) rate
Time Frame: Up to 36 months
Overall CR rate is defined as the percentage of participants achieving a CR at any time post-treatment. It will be measured by determining the percentage of participants without presence of high-grade disease using results from cystoscopy and centrally read urine cytology at any time point.
Phase II Arm 2: disease-free survival (DFS)
Time Frame: Up to 36 months
DFS will be measured as the time from the date of first dose of study treatment to either the time of the first recurrence of high-risk disease, progression, or death due to any cause, whichever occurs first.
Phase II Arm 3: event-free survival (EFS)
Time Frame: Up to 36 months
EFS will be measured as the time from the date of first dose of study treatment to either the time of the persistence of CIS after 6 months, the first recurrence of high-risk disease, progression, or death due to any cause, whichever occurs first.
Secondary Outcomes
- Phase I: Incidence and severity of treatment-emergent adverse events(Up to 36 months)
- Concentrations of Gemcitabine and 2',2' difluorodeoxyuridine (dFdU) in Urine and Plasma(up to 2 months)
- Phase I and Phase II Arm 3: overall complete response (CR) rate(Up to 36 months)
- Phase I and Phase II Arm 1 and Arm 3: duration of CR (DoR)(Up to 36 months)
- Phase I: disease-free survival (DFS)(Up to 36 months)
- Overall survival (OS)(Up to 36 months)