Intravesical GEM/DOCE for HR BCG-Unresponsive NMIBC

The primary objective of this study is to evaluate the efficacy of intravesical sequential Gemcitabine and Docetaxel in patients with BCG-unresponsive, high-grade, non-muscle-invasive bladder cancer (HG-NMIBC). Efficacy will be measured by the complete response (CR) rate at approximately 3 months for patients with carcinoma in situ (CIS), and by the disease-free rate from high-grade disease at 3 months for patients with high-grade papillary Ta/T1 disease. CR will be confirmed through cystoscopy, urine cytology, and bladder biopsy. Disease-free rate in patients with high-grade papillary disease will be assessed by non-positive cytology and the absence of visible tumor (biopsy optional).

Two distinct patient cohorts will be recruited for this trial:

Arm A: Patients with CIS, either alone or with concurrent papillary tumors Arm B: Patients with high-grade papillary tumors (Ta and/or T1) without CIS

Secondary objectives include characterizing the safety and toxicity profile of the treatment and evaluating additional efficacy outcomes such as high-grade recurrence-free survival (HGRFS), recurrence-free survival (RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), overall survival (OS), and quality of life (QoL).

The study will also assess outcomes in patients who experience early bladder cancer recurrence without progression and undergo a second 6-week induction cycle.

This is a prospective, two-arm, multicenter cohort study conducted nationally and internationally. Participants will receive intravesical Gemcitabine immediately followed by Docetaxel once weekly for 6 weeks (induction phase), followed by similar once monthly treatments for up to 24 months (maintenance phase). Patients will be followed for up to 5 years to assess long-term outcomes.

Inclusion criteria

Histologically confirmed diagnosis of urothelial carcinoma of the bladder without synchronous or metachronous upper tract involvement or prostatic urethral involvement. Subjects with negative upper tract imaging within 6 months of the study start and visually normal prostates are potentially eligible. Those with a history of suspicious upper tract cytology or suspicious prostatic urethra visually will require additional upper tract washes and/or biopsies to rule out concurrent extravesical disease.

Eligible bladder cancer presentations include:

• Carcinoma in situ (CIS), with or without non-muscle-invasive stage Ta or T1 tumors of any grade.
• High-Grade Papillary tumors (stages Ta and/or T1) without CIS.
• All visible bladder tumors must be completely resected within 8 weeks prior to initiating intravesical Gem/Doce therapy.
• If more than 8 weeks have passed since diagnosis or resection of index bladder CIS ± non-invasive tumor (pTa or T1 tumors), an office cystoscopy must be performed within 8 weeks of Gem/Doce initiation to confirm no visible tumor regrowth.

BCG-Unresponsive Disease as defined by any of the following FDA-accepted criteria:

• Occurrence of high-grade, stage T1 cancer after at least 5/6 weekly BCG induction treatments.
• Occurrence of CIS within 12 months, or high-grade papillary disease, stage Ta/T1, within 6 months after an "adequate" course of BCG therapy.

An "adequate" course of BCG includes at least 5/6 weekly BCG induction treatments and at least 2/3 weekly BCG maintenance or 2/6 weekly BCG re-induction treatments.

• N.B: Physician may have some flexibility (+/- 1 month) in the use of 6 and 12 months to define BCG-unresponsive NMIBC.
• N.B: Once a patient has been correctly defined as having BCG-unresponsive disease, they will be considered to always be BCG-unresponsive for the purpose of this study. In other words, there is no restriction as to when the BCG-unresponsive term was assigned.

• The occurrence of low-grade (LG) Ta disease will not be considered a HG relapse event given its prognosis is much more favorable that HG disease. However, all LG tumor must be completely resected before continuing with Gemcitabine/Docetaxel therapy.
• Subjects must be eligible for radical cystectomy and decline this standard of care treatment or not be a surgical candidate for radical cystectomy (as appropriate) based on other comorbidities.
• All grossly visible disease in the bladder must be fully resected with pathologic stage and grade assessed at the local study institution. Local pathologists are strongly encouraged to use the current LG and HG AJCC criteria.

NB: For institutions that still use the 3-tiered grading system, Ta Gr1 and Gr 2 will be considered LG while any Ta Gr3 or T1 Gr2 or Gr3 will be considered HG.

• Patients enrolled in other clinical trials must have received their last treatment at least 8 weeks prior to enrollment if the treatment was an intravesical agent. If the treatment included a systemic immune-modulating agent (e.g. anti-PD(L)-1 or anti CTLA4) then at least two dosing intervals must have elapsed untreated before the patient is eligible.
• Age > 18 and must be able to read, understand and sign the local informed consent.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance Status of 2 or less, including patients who are not surgical candidates due to comorbid conditions.
• Women of childbearing potential must have a negative pregnancy test at screening.
• All patients of childbearing potential must be willing to consent to using effective contraception, i.e., IUD, Birth control pills, Depo-Provera, and/or condoms while on treatment and for 3 months after their last Gemcitabine/Docetaxel treatment.
• No intravesical or upper tract topical therapy within 8 weeks of study entry.
• Must be willing and able to comply with all protocol requirements.
• Should have a Complete Blood Count (CBC) with differential before the index tumor resection or biopsy (within 30 days) and/or within 14 days before starting Gemcitabine/Docetaxel therapy.
• Must be willing and able to give informed consent and any authorizations required by the local Institutional Review Board (IRB) for participation in this study.

Exclusion criteria

• History or concurrent Stage T2 or greater urothelial cancer.
• History or concurrent upper tract or prostatic urethral cancer (no suspicious or positive upper tract cytology and negative upper tract imaging within 6 months of study entry; visually normal or absent prostatic urethra by cystoscopy).
• History or concurrent variant bladder cancer histology including squamous cell carcinoma, adenocarcinoma, small cell carcinoma, plasmacytoid carcinoma, nested urothelial carcinoma, sarcomatoid carcinoma, squamous, glandular, metastatic carcinoma and others. Select urothelial carcinoma with favorable micropapillary differentiation is permitted (see above).
• Active other malignancies excluding indolent or well-controlled prostate cancer, basal or squamous cell skin cancers or non-invasive cancer of the cervix are permitted so long as they are not expected to impact 3-year survival outcomes.
• History of severe hypersensitivity reaction (>= grade 3) to Gemcitabine and/or Docetaxel.
• History of severe hypersensitivity reaction (>= grade 3) to Polysorbate 80 containing drugs (Docetaxel is formulated with Polysorbate 80)
• Concurrent treatment with any intravesical or systemic chemotherapeutic agent (8-week washout required).
• Treatment with a checkpoint inhibitor within 2 treatment cycles of enrollment.
• Major surgery within 3 months of enrollment.
• Inadequate organ and bone marrow function as evidenced by:

• Hemoglobin ≤8.0 g/dL.
• Absolute neutrophil count ≤1.5 x 109/L.
• Platelet count ≤80 x 109/L.
• AST/SGOT and/or ALT/SGPT ≥3.0 x ULN.
• Total bilirubin >1.5 x ULN excepting known benign Gilbert's Disease.
• Serum creatinine >2.0 x ULN.

i. If creatinine 1.5 - 2.0 x ULN, creatinine clearance will be calculated according to CKD-EPI formula and patients with creatinine clearance <30 mL/min should be excluded.

• History of radiation to the pelvis.
• History of difficult catheterization that in the opinion of the Investigator will prevent safe and/or reliable administration of the intravesical agents.
• History of interstitial cystitis or current inability to hold ~ 2 ounces of fluid in the bladder for the expected 60-minute retention time (assistive medication and/or techniques (gravity reflux; split dosing) are permitted).
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy (3- week documented clearance required).
• Known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
• Recent Covid infection within 30 days of enrollment or currently symptomatic of Covid-related illnesses.
• Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).
• Women who are pregnant or lactating.
• Participation in any other research protocol involving administration of an investigational agent within 6 weeks of study entry (8-week washout required)
• Any other major or unstable medical condition that in the Investigator's opinion, could affect patient performance status, ability to receive the intravesical therapy and/or life expectancy during the five years of intended study participation.