A Study of HS-10566 in Patients With High-risk Non-muscle-invasive Bladder Cancer Who Are Ineligible for or Refuse Radical Cystectomy

Official title

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

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.

Interventions

• Drug HS-10566
  HS-10566 is an intravesical gemcitabine delivery system available in two drug-loaded strengths: 0.3 g gemcitabine and 0.6 g gemcitabine.
• Drug HS-10566
  HS-10566 is an intravesical gemcitabine delivery system available in two drug-loaded strengths: 0.3 g gemcitabine and 0.6 g gemcitabine.
• Drug HS-10566
  HS-10566 is an intravesical gemcitabine delivery system available in two drug-loaded strengths: 0.3 g gemcitabine and 0.6 g gemcitabine.

Primary outcome measures

• Phase I: RP2D [Time frame: Up to 5 months]
• Phase II Arm 1: overall complete response (CR) rate [Time frame: Up to 36 months]
• Phase II Arm 2: disease-free survival (DFS) [Time frame: Up to 36 months]
• Phase II Arm 3: event-free survival (EFS) [Time frame: Up to 36 months]

Secondary outcome measures (6)

• Phase I: Incidence and severity of treatment-emergent adverse events [Time frame: Up to 36 months]
• Concentrations of Gemcitabine and 2',2' difluorodeoxyuridine (dFdU) in Urine and Plasma [Time frame: up to 2 months]
• Phase I and Phase II Arm 3: overall complete response (CR) rate [Time frame: Up to 36 months]
• Phase I and Phase II Arm 1 and Arm 3: duration of CR (DoR) [Time frame: Up to 36 months]
• Phase I: disease-free survival (DFS) [Time frame: Up to 36 months]
• Overall survival (OS) [Time frame: Up to 36 months]

Eligibility criteria

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.
• HR-NMIBC patients who have not received BCG therapy after TURBT, and who refuse or are ineligible for BCG instillation as determined by the investigator. Ineligibility for BCG includes, but is not limited to: active tuberculosis, severe hematuria, recent traumatic catheterization, symptomatic urinary tract infection, immunodeficiency or impairment (e.g., AIDS, patients receiving immunosuppressants or radiotherapy), BCG hypersensitivity, etc.
• 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.

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.
• Systemic chemotherapy, small-molecule targeted therapy, or investigational therapy within 4 weeks before first study treatment.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Peking University First Hospital — Beijing
• Nanjing Drum Tower Hospital — Nanjing

Identifiers

NCT: NCT07468851 · HS-10566-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗