Prospective Phase II Study to Evaluate Response to Two Induction Courses (12 intravesical instillations) of BCG Therapy for High-Risk Non-Muscle-Invasive Bladder Cancer

TPS4591 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. Results: If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Conclusion:Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial information: NCT02844816.

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Hypo-Fractionated Radiotherapy Boost And Concurrent Chemo-Radiotherapy For Patients With Muscle-Invasive Bladder Cancer (MIBC): A Preliminary Report Of The Prospective Phase II Study

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2020.07.507 ◽

2020 ◽

Vol 108 (3) ◽

pp. e896

Author(s):

S.B. Qin ◽

X.S. Gao ◽

C.J. Zhang ◽

H.Z. Li ◽

L. Yao

Keyword(s):

Bladder Cancer ◽

Phase Ii ◽

Preliminary Report ◽

Phase Ii Study ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Fractionated Radiotherapy ◽

Prospective Phase ◽

Muscle Invasive

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Transurethral Resection of Bladder Tumor (TURBT) Followed By Partial Hypo-Fractionated Radiotherapy Concurrent with Chemotherapy for Patients with Muscle-Invasive Bladder Cancer (MIBC): Acute Toxicities of a Prospective Phase II Study

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.06.1948 ◽

2019 ◽

Vol 105 (1) ◽

pp. E252-E253

Author(s):

S.B. Qin ◽

X.S. Gao ◽

C.J. Zhang ◽

H.Z. Li ◽

L. Yao

Keyword(s):

Bladder Cancer ◽

Phase Ii ◽

Transurethral Resection ◽

Bladder Tumor ◽

Phase Ii Study ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Fractionated Radiotherapy ◽

Prospective Phase ◽

Muscle Invasive

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Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.5022 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 5022-5022 ◽

Cited By ~ 5

Author(s):

Peter C. Black ◽

Catherine Tangen ◽

Parminder Singh ◽

David James McConkey ◽

Scott Lucia ◽

...

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Phase Ii ◽

Complete Response ◽

Median Number ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Bladder Preservation ◽

Bcg Therapy ◽

Muscle Invasive

5022 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 in NMIBC after BCG therapy, this trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report on the subset with CIS (with or without concomitant Ta/T1) among patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate at 6 months as defined by mandatory biopsy with a null hypothesis of 30% and alternative of 50% with a 1-sided alpha = 0.05 and 96% power. The 3 month CR rate, defined by cytology, cystoscopy and for-cause biopsy, is reported here as a secondary endpoint, in addition to safety. Results: Seventy-five eligible CIS patients were enrolled. Two received no treatment and are not evaluable. Of 73, median patient age was 73.4 years and median number of prior BCG doses was 12. Concomitant Ta/T1 tumor was found in 30 (41.1%) patients, including T1 disease in 16 (21.9%). A CR was observed in 30 (41.1%; 95% CI 29.7%, 53.2%) patients at 3 months and 19 (26.0%; 95% CI 16.5%, 37.6%) at 6 months. Any possibly or probably treatment-related adverse event (AE) was observed in 61 (83.6%) patients. The most frequent AEs were fatigue 36 (49.3%), pruritis 8 (11.0%), hypothyroidism 8 (11.0%), and nausea 8 (11.0%). Grade 3-5 AEs occurred in 9 (12.3%) patients and there was one treatment-related death (myasthenia gravis with respiratory failure and sepsis). Conclusion: The observed response to atezolizumab at 3 and 6 months in patients with BCG-unresponsive CIS was similar to that reported in recent similar trials and meets the benchmark for initial CR defined by the FDA guidance. This trial provided no new safety concerns. The duration of response will determine if this is a suitable treatment option for patients with BCG-unresponsive high risk CIS. Clinical trial information: 02844816 .

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