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

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5022-5022 ◽  
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 .

S1605: Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4591-TPS4591 ◽  
Author(s):  
Parminder Singh ◽  
Tangen Catherine ◽  
Seth P. Lerner ◽  
David McConkey ◽  
Melissa Plets ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Invasive Bladder Cancer ◽  
Type I ◽  
Muscle Invasive Bladder Cancer ◽  
Primary Endpoints ◽  
Bcg Therapy ◽  
Muscle Invasive

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.

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

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4541-4541
Author(s):  
Peter C. Black ◽  
Catherine Tangen ◽  
Parminder Singh ◽  
David James McConkey ◽  
Scott Lucia ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Phase Ii ◽  
Statistical Power ◽  
Unmet Need ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Bladder Preservation ◽  
Duration Of Response ◽  
Muscle Invasive

4541 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. 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 the 18 month results for all eligible patients who received at least one protocol treatment. The co-primary endpoints were pathological complete response (CR) rate at 6 months in patients with CIS (reported at ASCO 2020), and event-free survival (EFS) in all patients at 18 months using Kaplan-Meier methods (KM), conditional on a positive CIS response rate. A sample size of 135 evaluable patients provided 93% statistical power for detecting a 30% 18-month EFS rate versus 20% using a one-sided alpha = 0.05. EFS in the subset with Ta/T1 disease and duration of response in CIS patients were secondary endpoints. Results: 172 patients were enrolled, 166 received at least one dose of atezolizumab and are included in the safety analysis, and, of those, 128 were eligible and included in the efficacy analysis. As previously reported, 20 (27%) out of 74 patients with CIS attained a pathologic CR at 6 months. The KM estimate of 12 month (actual 11.9 mo) duration of response after 6 month CR for CIS patients was 54% (95% CI 30%, 78%) and the median duration of response was 16.5 months. The KM EFS rate at 18 months in 74 patients with CIS was 17% (90% CI 9%, 25%). The 18 month KM EFS rate in the overall population of 128 patients with Ta, T1 and CIS was 29% (90% CI 22%, 36%). The 18 month actuarial EFS rate in 54 patients with Ta/T1 disease was 45% (90% CI 34, 57%). Any possibly or probably treatment-related adverse event (TRAE) was observed in 142 out of 166 (86%) patients who received any atezolizumab regardless of eligibilty. The most frequent TRAEs were fatigue 72 (43%), diarrhea 34 (20%), and anemia 38 (23%). Grade 3-5 TRAEs occurred in 28 (17%) patients, including rash in 4 (2%), hyponatremia in 4 (2%), hypertension in 3 (2%) and elevated liver function tests in 3 (2%). There were two treatment-related deaths (sepsis and respiratory failure due to myasthenia gravis). Conclusions: The observed response of atezolizumab at 6 and 18 months in patients with BCG-unresponsive CIS suggests that this could be a valuable treatment to address a critical unmet need in this patient population. The 18 month EFS in patients with Ta/T1 disease suggests activity in this patient subset. This trial provided no new safety concerns. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, CA180863 and in part by Genentech. Clinical trial information: NCT02844816.

A phase I trial for the use of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) in the treatment of BCG-refractory nonmuscle invasive urothelial carcinoma of the bladder.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 313-313 ◽  
Author(s):  
Guarionex Joel DeCastro ◽  
Wilson Sui ◽  
Jamie S. Pak ◽  
Corinne T. Abate-Shen ◽  
Shing Mirn Lee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Complete Response ◽  
Median Number ◽  
Salvage Chemotherapy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
First Line Therapy ◽  
Muscle Invasive ◽  
Gemcitabine And Cisplatin

313 Background: Salvage intravesical chemotherapy has shown benefit in patients with high-risk non-muscle invasive bladder cancer who fail first line therapy. Our preclinical murine intravesical trial showed a combination therapy was superior to single-agents. Our objective was to investigate the safety of intravesical triple agent salvage chemotherapy consisting of cabazitaxel, gemcitabine and cisplatin (CGC). Methods: Patients with BCG refractory or recurrent high-risk non-muscle invasive bladder cancer who refused radical cystectomy were enrolled. All patients underwent a pre-treatment transurethral resection of bladder tumor and then received a 6-week regimen. All patients received the same dose of gemcitabine (2000mg) while the dose of cisplatin and cabazitaxel were escalated as shown in table 1. Toxicity was categorized according to CTC for Adverse Events v4 and included hematuria, dysuria, bladder spasm, urinary retention or frequency. A complete response (CR) was defined as a negative random bladder biopsy and negative cytology six weeks after treatment. Results: Median age of the 9 patients was 74 years (table 1) and the median number of prior intravesical therapies was 4 (range 2-5). All patients completed 6 weeks of induction CGC. Any local toxicity was found in 7 patients with 5 experiencing at least 1 grade 1 toxicity and 4 experiencing at least 1 grade 2 toxicity. Seven of eight patients were complete responders and initiated maintenance therapy. Conclusions: CGC appears to be a well-tolerated intravesical salvage chemotherapy regimen for the treatment of BCG-refractory NMIBC. Clinical trial information: NCT02202772. [Table: see text]

Efficacy of chemohyperthermia (HIVEC) in patients with high-risk nonmuscle invasive bladder cancer (NMIBC) who fail BCG therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 456-456
Author(s):  
Geraldine Pignot ◽  
Laure Doisy ◽  
Jochen Walz ◽  
Thibault Marquette ◽  
Thomas Maubon ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Invasive Disease ◽  
Invasive Bladder Cancer ◽  
Bladder Preservation ◽  
Bcg Therapy ◽  
Risk Of Progression ◽  
Muscle Invasive ◽  
Preservation Rate ◽  
Very High

456 Background: To evaluate Hyperthermic Intra-Vesical Chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (DFS) rate and bladder preservation rate in patients with high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who fail BCG therapy or are contraindicated to BCG. Methods: Between June 2016 and October 2019, patients treated with HIVEC for high-risk NMIBC who failed BCG (Fail-BCG) or BCG-naive if BCG contraindicated (N-BCG) have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. Results: Fifty-three patients, median age 72 [39-93] years, were included (n = 29 Fail-BCG and n = 24 N-BCG). The median follow-up was 18 months. The bladder preservation rate was 92.4%. The RFS rate at 12 months was 60.5%. The RFS rate at 12 months for N-BCG and Fail-BCG groups was respectively 70% and 52.2%. Three patients progressed to muscle-invasive disease, all in the Fail-BCG group and all in the very high-risk EORTC group. Two of them experienced metastatic progression and died from bladder cancer. Conclusions: Chemohyperthermia using HIVEC device achieved a RFS rate of 60% at 1 year and enabled a bladder preservation rate of 92%. Given the low risk of progression in the N-BCG group, HIVEC could be a good alternative. Conversely, for patients with very high-risk tumors that fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.

Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy as bladder-sparing therapy in patients with localized muscle invasive bladder cancer: A SOGUG study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5097-TPS5097
Author(s):  
M. Andres Cuellar ◽  
Ana Medina ◽  
Regina Girones ◽  
B.P. Valderrama ◽  
Albert Font ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bladder Cancer ◽  
Phase Ii ◽  
External Beam Radiotherapy ◽  
Human Monoclonal Antibody ◽  
Pathological Response ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Bladder Preservation ◽  
Muscle Invasive

TPS5097 Background: Several studies have shown that long-term bladder preservation is feasible in selected patients with muscle-invasive bladder cancer, using a multimodal treatment, including transurethral resection (TUR), radiotherapy and chemotherapy. Durvalumab, a fully human monoclonal antibody against PD-L1, has shown activity in patients with advanced pretreated urothelial cancer. A preclinical study showed that the combination of radiation, anti-CTLA4 and anti-PD-L1 overcome- adaptive immune resistance and has superior activity than either therapy alone (Twyman-Saint Victor et al. Nature 2015). The purpose of the present study is to explore feasibility, toxicity and activity in terms of response and bladder preservation of the integration of TUR, immune double checkpoint inhibition with durvalumab and tremelimumab (a fully human monoclonal antibody against CTLA-4), and radiotherapy in the treatment of localized muscle-invasive. Methods: This is a multicenter prospective phase II study of multimodal therapy in patients with localized urothelial carcinoma of the bladder in clinical stages T2-4a N0 M0, ECOG 0- 1, without contraindications to immunotherapy, who either wish for bladder preservation or are ineligible for cystectomy. The primary endpoint is pathological response (≤T1) at post-treatment biopsy. A 2-stage sequential design (response rate P0=5, P1=0.7, α=0.10, β=0.20) requires at least 6 responses in the first 12 pts to expand to a second cohort of 20 patients. The treatment consists of initial TUR of the tumor, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam radiotherapy is started 2 weeks later, at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. Patients with pathological response will be candidates to bladder preservation, whereas those with residual muscle invasive tumor will be candidates to salvage cystectomy. At present time, prespecified activity goal for the first stage of accrual was met; second stage accrual began in December 2019. Clinical trial information: NCT03702179 .

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