A Phase 3 Study of Cretostimogene Grenadenorepvec in Patients With Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus-Calmette-Guerin (BCG)
This is a Phase 3, open-label, single arm trial designed to evaluate Cretostimogene patients with NMIBC who have failed prior BCG therapy. Up to approximately 115 CIS bladder cancer patients with or without HG Ta or HG T1 papillary disease will be enrolled under the original protocol through Amendment 4, which will comprise Cohort C. Cohort C is closed to enrollment. Under Amendment 5-1, Cohort P was added to enroll up to 70 patients with HG Ta/T1 papillary bladder cancer. Under Amendment 6, the target number of patients enrolled in Cohort P was increased to 75. Cohort P is open to enrollment Cohort C and Cohort P will be analyzed and reported separately. Patients will have had to fail prior BCG therapy which is defined as having persistent or recurrent disease within 12 months (Cohort C) or 6 months (Cohort P) following the completion of adequate BCG therapy for HGUC
∙ In order to be eligible for participation in this trial, the patient must:
• Be ≥18 years of age (or legal age of majority in the jurisdiction) on day of signing informed consent.
• Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Have pathologically confirmed (WHO grading system employed for tumor grading) (Compérat 2019) BCG unresponsive CIS. Patients with BCG unresponsive CIS are those unlikely to benefit from, and who will not be receiving, further intravesical BCG. There is no maximum limit to the amount of prior BCG treatment, but maintenance BCG should be administered on a schedule consistent with standard induction-maintenance protocols (e.g., BCG weekly × 6 then weekly × 3 weeks administered at Months 3, 6, 12, 18, 24, and 36). Specifically, the definition of BCG unresponsive CIS will also require the following:
‣ Pathologically confirmed relapsed or persistent CIS (with or without HG Ta or HG T1 disease) within 12 months of completion (last dose) of adequate BCG treatment for HGUC (e.g., CIS, HG Ta, HG T1, or a combination of these HGUC pathologies).
⁃ Completion of qualifying BCG treatment (e.g., 5+2 minimum exposure) within 12 months of the initial qualifying dose of BCG (e.g., induction and initial maintenance or re-induction cycle must be completed over no more than a 12-month period of time).
⁃ Pathological confirmation of BCG unresponsive CIS within 8 weeks of study enrollment.
⁃ CIS specimen must be predominantly urothelial (transitional cell) and have less than 50% variant (e.g., sarcomatoid, squamous etc. component) histology.
⁃ No maximum limit to the amount of BCG administered but maintenance BCG should be administered on a schedule consistent with the SWOG 8507 regimen (Lamm 2000).
• Have all Ta and/or T1 disease resected and all CIS resected or fulgurated, as feasible, prior to study treatment (e.g., prior to Day 1 treatment).
• Ineligible to receive radical cystectomy (medically unfit) or refusal of radical cystectomy according to Investigator assessment.
• Demonstrate adequate organ function
• Patients must be willing to comply with study mandated cystoscopies, urine cytology, urograms, biopsies, and other procedures (including TURBT or other resection for all Ta/T1 disease) for the duration of the study. Patients who withdraw consent for these procedures will be withdrawn from the trial
• Be ≥18 years of age (or legal age of majority in the jurisdiction) on day of signing informed consent
• Have ECOG performance status of 0 to 2.
• Have pathologically confirmed (WHO grading system employed for tumor grading) (Compérat 2019) BCG-unresponsive HG Ta/T1 papillary disease without CIS. Patients with BCG-unresponsive HG Ta/T1 papillary disease are those unlikely to benefit from and who will not be receiving further IVE BCG. There is no maximum limit to the amount of prior BCG treatment, but maintenance BCG should be administered on a schedule consistent with standard induction-maintenance protocols. Specifically, the definition of BCG unresponsive HG Ta/T1 papillary disease without CIS will also require the following:
‣ Pathologically confirmed recurrent HG Ta/T1 papillary disease without CIS within 6 months of completion (last dose) of adequate BCG treatment for HGUC (e.g., CIS, HG Ta, HG T1, or a combination of these HGUC pathologies).
⁃ Patients with HG Ta: Completion of qualifying BCG treatment (e.g., 5+2 minimum exposure) within 12 months of the initial qualifying dose of BCG (e.g., induction and initial maintenance or re-induction cycle must be completed over no more than a 12-month period of time).
⁃ Patients with HG T1: Patients may be eligible after the initial induction alone (5 of 6 doses of an induction course) as the qualifying BCG treatment.
⁃ Completion (last dose) of qualifying BCG treatment within 12 months of study enrollment.
⁃ Pathological confirmation of BCG-unresponsive HG Ta/T1 papillary disease without CIS within 14 days of study enrollment.
⁃ All pathology specimens must be predominantly urothelial (transitional cell) and have less than 50% variant (e.g., sarcomatoid, squamous etc. component) histology.
⁃ No maximum limit to the amount of BCG administered; however, there should be no more than 12 months between cycles of BCG
• Have all Ta and/or T1 disease resected, prior to study treatment (e.g., prior to Day 1 treatment).
• Ineligible to receive radical cystectomy (medically unfit) or refusal of radical cystectomy based on Investigator assessment.
• Demonstrate adequate organ function,
• Patients must be willing to comply with study-mandated cystoscopies, urine cytology, imaging, biopsies, and other procedures for the duration of the trial