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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 180
- 试验地点
- 4
- 主要终点
- Phase I: RP2D
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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;
- •Recurrence of high-grade T1 tumors at the first assessment during maintenance therapy after 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 have not received BCG.
- •HR-NMIBC patients who have not received BCG therapy after TURBT.
- •HR-NMIBC patients who received prior BCG therapy but discontinued treatment for more than 3 years before enrollment.
- •Participants must have undergone TURBT within 12 weeks prior to signing informed consent and meet the following criteria:
- •For papillary lesions (Ta and T1 stages): complete resection of all visible papillary lesions, with negative urine cytology (including atypical findings).
- •For patients with CIS: residual unresectable CIS lesions are permitted.
- •Sufficient bone marrow reserve and adequate hepatic/renal function.
- •Eastern Cooperative Oncology Group (ECOG) performance status score 0-1.
排除标准
- •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.
- •Systemic chemotherapy, small-molecule targeted therapy, or investigational therapy within 4 weeks before first study treatment.
- •Device-assisted chemotherapy (e.g. TAR-200)
- •Residual toxicity ≥ Grade 2 per CTCAE version 6.0 from prior therapy (surgery, intravesical instillation, etc.), except alopecia, pigmentation.
- •Bladder or urethral anatomical features that may interfere with HS-10566 implantation, retention, or removal (e.g., urethral stricture, bladder diverticulum, total urinary incontinence, bladder perforation).
- •Current or history of clinically significant polyuria (24-hour urine output >4000 mL).
- •Requirement for long-term indwelling urinary catheter during study treatment (e.g., urinary obstruction).
- •Intermittent catheterization for clinical indications is allowed.
研究组 & 干预措施
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).
干预措施: HS-10566 (Drug)
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).
干预措施: 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).
干预措施: HS-10566 (Drug)
结局指标
主要结局
Phase I: RP2D
时间窗: Up to 5 months
Phase II Arm 1: overall complete response (CR) rate
时间窗: 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)
时间窗: 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)
时间窗: 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.
次要结局
- 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)