Clinical Trials Corner

Dear Readers,

The Clinical Trials Corner of the Bladder Cancer journal is a section devoted towards highlighting ongoing trials or recently completed trials in urothelial cancer. Our hope is to encourage accrual for ongoing trials and to educate readers on the results of completed trials. If you feel that you would like to draw attention to a specific trial, please feel free to email us at: pkagarwal@uchicago.edu and/or cns9006@med.cornell.edu.

Sincerely,

Piyush K. Agarwal Cora N. Sternberg
Piyush K. Agarwal, MD Cora N. Sternberg, MD, FACP
Associate Editor, Bladder Cancer Associate Editor, Bladder Cancer
Director, Bladder Cancer Program Clinical Director, Englander Institute of Precision Medicine
University of Chicago Medicine Weill Cornell Medicine
Chicago, IL, USA New York, NY, USA

Phase III Randomized Trial of Concurrent Chemoradiotherapy With or Without Atezolizumab in Localized Muscle Invasive Bladder Cancer

Status: 
Recruiting
Sponsor: 
National Cancer Institute/SWOG/Alliance/ECOG-ACRIN
Enrollment: 
475
Study Design: 
This is a randomized trial for patients with localized muscle-invasive bladder cancer who have refused or are unfit for radical cystectomy whereby patients are randomized to radiation therapy (three-dimensional conformal or intensity-modulated) with chemotherapy as per the treating physician with or without atezolizumab. The chemotherapy can consist of either gemcitabine, cisplatin, or fluorouracil and mitomycin. Patients treated in the atezolizumab arm are treated every 3 weeks for up to 6 months.
Rationale: 
Chemoradiation has an established therapeutic role in localized muscle-invasive bladder cancer. This trial is designed to understand the potential of immunotherapy, specifically atezolizumab, to enhance the bladder intact even-free survival rate with chemoradiation.
Endpoints: 
The primary outcome is bladder intact event-free survival (BI-EFS) rate for up to 5 years. This composite endpoint includes the absence of muscle invasive bladder recurrence, regional pelvic soft tissue or nodal recurrence, distant metastases, bladder cancer or toxicity related death or cystectomy). Secondary endpoints include: overall survival at 5 years, disease-specific survival, NMIBC recurrence rate, cystectomy rate, and several immunologic and biologic endpoints.
Comments: 
This trial is ambitious and the criteria for tradiational chemoradiation or trimodal therapy has been expanded in this trial to allow patients with unilateral hydronephrosis and non-diffuse CIS to be enrolled. These clinical features are typically associated with poor response to bladder-sparing therapy so it will be interesting to see how the addition of atezolizumab impacts patients with these features on the trial. The correlatives are extensive and may provide clues towards prediction of responses.
Results: 
This trial is actively accruing patients and has accrued 119 of the 475 planned enrollment.

Phase II Trial of Intravesical Gemcitabine and MK-3475 (Pembrolizumab) in the Treatment of Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer

Status: 
Recruiting
Sponsor: 
National Cancer Institute/Alliance
Enrollment: 
161
Study Design: 
This is a multicenter Alliance cooperative group trial in which BCG unresponsive NMIBC patients who refuse or are unfit for radical cystectomy undergo weekly gemcitabine intravesical instillation for 6 weeks during the first 2 cycles of concurrent IV pembrolizumab every three weeks until week 10. Patients are then evaluated with cystoscopy and cytology in Week 13 and if no evidence of disease, they then continue to receive both intravesical gemcitabine and systemic pembrolizumab concurrently every 3 weeks with cystoscopy and cytology every 3 months. Mandatory biopsies are performed in the CIS containing cohort at 6 months and all patients undergo an end of study cystoscopy and cytology at 18 months.
Rationale: 
The current gold standard treatment for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is radical cystectomy. However, many patients refuse radical cystectomy and some are unfit for surgery and therefore are treated with various regimens of intravesical chemotherapy or clinical trials. Until recently, many patients in this group were treated with single-agent gemcitabine based on prospective series demonstrating less disease recurrence in patients treated with gemcitabine compared with BCG again in BCG-refractory high grade NMIBC. The recent approval of pembrolizumab as a single-agent for BCG-unresponsive CIS has also widened the therapeutic options for these group of patients. This trial evaluates the combination of both gemcitabine and pembrolizumab in BCG-unresponsive high grade NMIBC (Ta, T1, and/or CIS).
Endpoints: 
There are dual primary endpoints: 6-month complete response rate for patients with a CIS tumor component and 18-month event-free survival rate for all patients. An interim analysis will be performed after 37 patients and at least 12 complete responses are required in order to proceed with the trial. The null hypothesis is a 30% 6-month complete response rate and a 25% 18-month event-free survival rate.
Comments: 
With efficacy of both agents as single therapies, there is optimism that some synergy will be noted with the combination approach. Unfortunately with the disease space of BCG unresponsive NMIBC crowded with several clinical trials, this trial may not be getting the much needed attention it deserves.There is great interest in immunotherapy in all stages of bladder cancer and it is hoped that prolonged responses can occur and patients will be able to maintain their bladders . Chemotherapy promotes tumor immunity by inducing immunogenic cell death as part of its intended therapeutic effect, and by disrupting strategies that tumors use to evade immune recognition. Chemotherapy may be able to stimulate neoantigens that would make immunotherapy more effective. Given the popularity of the combination off label approach of gemcitabine and docetaxel for BCG-unresponsive NMIBC, supporting this potentially practice changing trial is important in order to understand the role of combination therapy.
Results: 
The trial has only accrued 10 of the planned 161 patients and a safety run-in was performed on the first 6 patients and no adverse events were noted. Unfortunatley, the trial was temporarily suspended during the COVID-19 pandemic but is now open for accrual at many centers.

A Phase II Study of Dose-Dense Gemcitabine Plus Cisplatin (ddGC) in Patients With Muscle-Invasive Bladder Cancer With Bladder Preservation for Those Patients Whose Tumors Harbor Deleterious DNA Damage Response (DDR) Gene Alterations

Status: 
Recruiting
Sponsor: 
National Cancer Institute/Alliance
Enrollment: 
271
Study Design: 
This trials enrolls patients with histologically confirmed MIBC (cT2-T4aN0/xM0) disease on TURBT and sequences their tumors with MSK-IMPACT. All patients are treated with dose-dense gemcitabine and cisplatin (undergoing current amendment to be given at investigator’s discretion with six cycles over 12 weeks or 4 cycles over 12 weeks). Patients with deleterious alterations in at least one or more DDR genes can undergo repeat TURBT and if residual disease is cT0 or CIS, patients can undergo bladder-sparing (observed without additional therapy). Patients with cT1 disease or greater will go on to receive chemoradiation or radical cystectomy. Patients without deleterious alterations in DDR genes will have an option to either undergo chemoradiation or radical cystectomy.
Rationale: 
Bladder preservation is an important topic to address in patients witn muscle invasive bladder cancer (MIBC). Some prospective series have demonstrated a subset of patients with MIBC who have experienced a complete response to neoadjuvant chemotherapy and who have remained free of disease. Patients whose tumors harbor deleterious DNA Damage Response (DDR) Gene Alterations have a greater chance of responding to cisplatin based chemotherapy and obtaining a complete response, perhaps avoiding cystectomy. This trial prospectively tests this hypothesis in patients with MIBC.
Endpoints: 
The primary endpoint is 3-year event-free survival in the bladder-sparing group which is defined as the proportion of patients without invasive or metastatic recurrence following definitive dose-dense gemcitabine and cisplatin chemotherapy in those patients whose pre-treatment TURBT tumors harbored DDR gene alterations and who achieved <cT1 response to chemotherapy. The secondary endpoint is the pT0 and <pT2 rate in all patients who ultimately undergo a radical cystecdtomy.
Comments: 
This trial is very similar to a trial being conducted at Fox Chase Cancer Center and both test the premise that DDR alterations (genes such as ERCC2, ERCC5, BRCA1, BRCA2, RAD51C, ATR, ATM, FANCC, and RECQL4) in MIBC can predict for patients that might be exceptional responders to chemotherapy. We eagerly await this intelligent strategy for selection of patients for bladder-sparing. Questions still linger regarding the development of MIBC and the potential aggressiveness of any resulting NMIBC in the patients that undergo bladder sparing and have a NMIBC recurrence.
Results: 
This trial is still accruing and has enrolled at least 91 patients to date.

Phase II Open Label, Study of IMMU-132 in Metastatic Urothelial Cancer After Failure of Platinum-Based Regimen or Anti-PD-1/ PD-L1 Based Immunotherapy (TROPHY-U-01 Cohort 1)

Status: 
Open
Sponsor: 
Immunomedics, Inc.
Enrollment: 
201
Study Design: 
This was a phase II, multicenter single-arm trial and updated data for the cohort of 113 patients with metastatic UC that progressed on prior platinum and immune checkpoint therapy were presented at ESMO 2020. Patients received IMMU-132 10mg/kg days 1 and 8 of a 21-day cycle that was continued until toxicity or disease progression. The null hypothesis was an overall response rate 12%.
Rationale: 
Although patients with metastatic UC have multiple options for therapy, patients who do not respond to platinum-based chemotherapy and/or anti-PD-1/PD-L1 based immunotherapy have had few treatment options until recently (enfortumab vedoin and erdafitinib). Antibody-drug conjugates (ADCs) are monoclonal antibodies (mABs) conjugated to cytotoxic drugs that can deliver a toxic payload to tumor cells expressing a specific tumor target. Enfortumab vedotin is a well-known ADC targeting Nectin 4 that is now FDA-approved. In this specific trial, a different ADC, Sacituzumab govitecan (SG), also known as IMMU-132, is evaluated containing an antibody against the epithelial cell surface molecule Trop-2 conjugated SN-38 (a potent derivative of the cytotoxic drug irinotecan). Trop-2 is overexpressed in bladder cancer and SN-38 inhibits DNA topoisomerase 1 thereby preventing DNA unwinding which results in irreversible double strand DNA breaks and eventually cytotoxic cell death. SG is distinct from other ADCs, with a high drug-to-antibody ratio.
Endpoints: 
The primary objective was overall response rate (ORR) and the secondary outcomes are duration of response (DOR), PFS and OS.
Comments: 
The results are encouraging given the fact that the patients were heavily pre-treated. In fact, 10 patients in the cohort were previously treated with enfortumab vedotin and despite that 3 of these patients had a partial response to SG. ADCs may represent a new salvage therapy option for patients with metastatic UC with progression after checkpoint inhibition therapy and chemotherapy.
Results: 
The group was heavily pre-treated with a median number of 3 prior anti-cancer therapies and the median age of the cohort was 66. There was a 27% overall response rate. The median duration of response was 5.9 months and 76% of patients had a reduction in tumor size. As of data cut-off, 16 of the 113 patients were continuing on treatment. Overall two-thirds of patients discontinued therapy due to progressive disease. Median PFS was 5.4 months and median OS was 10.5 months. Of note, 28% of patients had liver metastases. The most common treatment-related adverse event was diarrhea with 9% of patients having a grade 3 event.

Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with carboplatin/gemcitabine (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy (

Status: 
Open
Sponsor: 
Associació per a la Recerca Oncologica, Spain
Enrollment: 
85
Study Design: 
This is a phase II multicenter, randomized trial evaluating the safety and efficacy of the combination of avelumab plus carboplatin/ gemcitabine versus carboplatin/ gemcitabine alone in patients with metastatic UC who have not received prior systemic therapy and are cisplatin ineligible. Patients had to have an ECOG status of 0-2 and patients received 6 cycles of carboplatin/gemcitabine with or without avelumab which was given as induction (2 cycles avelumab), concurrent with chemotherapy (6 cycles), and as maintenance in the group that received it with the chemotherapy. Avelumab maintenance was continued until progression, unacceptable toxicity, or treatment discontinuation.
Rationale: 
Up to 50% of patients with metastatic urothelial carcinoma (mUC) are not eligible for cisplatin. Carboplatin has activity but not comparable and so this trial evaluates whether Avelumab given as an induction therapy and in combination with carboplatin/ gemcitabine results in superior anti-tumor activity compared to standard chemotherapy in cisplatin-ineligible patients with metastatic UC. Biologically, chemotherapies can induce immunogenic cell death which may enhance the ability of checkpoint inhibitors such as avelumab.
Endpoints: 
The primary endpoint was overall response rate (ORR) by RECIST criteria. The secondary endpoints included PFS, OS, duration of response (DoR), and safety and tolerability.
Comments: 
Induction immunotherapy followed by chemoimmunotherapy did not significantly improve outcomes in this trial. The trial is different than the findings seen in the Javelin 100 study which demonstrated superior OS in the maintenance arm with avelumab. However, this initial analysis is still immature and further follow-up is needed for definitive conclusions.
Results: 
The trial enrolled 42 patients in the chemoimmunotherapy arm and 42 patients in the chemotherapy alone arm. In an intention to treat analysis, the overall response rate was 57.1% versus 53.5% respectively, with no significant difference between the arms. Partial and complete responses were 45.2% and 11.9% in the chemoimmunotherapy arm compared with 44.2% and 9.3% in the chemotherapy arm. Median PFS was similar at 6.9 months versus 7.4 months (p=0.1356) in the chemoimmunotherapy versus chemotherapy arms respectively. Median OS was similar at 10.5 months versus 13.2 months (p=0.2642) in the chemoimmunotherapy versus chemotherapy arms respectively. Overall, the drugs were safe and tolerable with their usual expected toxicities.

A phase 3 randomized open label study of durvalumab with or without tremilumimab versus standard of care (SoC) chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE)

Status: 
Open
Sponsor: 
AstraZeneca
Enrollment: 
1032
Study Design: 
DANUBE is a randomized, phase 3 trial to evaluate durvalumab, with or without tremelimumab, vs platinum-based chemotherapy as a first-line treatment for metastatic UC. Patients were randomized 1:1:1 to Durvalumab 1500 mg q4w alone until progression (n=346) or Durvalumab plus Tremelimumab 75 mg q4w for up to 4 doses (n=342) or SoC chemotherapy (gemcitabine + cisplatin or carboplatin, up to 6 cycles) (n=344.)
Rationale: 
Platinum-based chemotherapy is the standard of care (SoC) for first-line treatment of metastatic UC. While chemotherapy regimens yield high response rates, survival outcomes are poor. Durvalumab (anti-PD-L1) is FDA approved for the treatment of platinum-refractory, metastatic UC. Tremelimumab (anti-CTLA-4) and the combination of durvalumab plus tremelimumab have shown activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.
Endpoints: 
The co-primary endpoints were OS comparing durvalumab monotherapy vs. chemotherapy groups among patients whose tumors had high PD-L1 expression and overall survival comparing durvalumab + tremelimumab vs. chemotherapy groups in the intention-to-treat (ITT) population.
Comments: 
The primary endpoints in his study were not met. With a median follow-up for survival of 41.2 months, this study has the longest follow-up to date for a randomized trial of an immunotherapy in previously untreated, metastatic UC. Further investigation of the combination in the context of checkpoint inhibitors may be warranted.
Results: 
The DANUBE trial did not meet either of the co-primary endpoints of overall survival. However, secondary analyses suggested that the combination of durvalumab + tremelimumab has activity, which is enhanced in patients with tumours that have high PD-L1 expression. This trial was a negative trial but it does suggest that a biomarker-based strategy should be tested in patients whose tumors are PD-L1 positive and may benefit from the combination of durvalumab + tremelimumab.

Pembrolizumab alone or combined with chemotherapy versus chemotherapy alone as first line therapy for advanced urothelial carcinoma (UC): Keynote 361

Status: 
Open
Sponsor: 
Merck Sharpe and Dohme
Enrollment: 
1010
Study Design: 
This was a global, randomized open label phase 3 trial comparing pembrolizumab alone or combined with platinum-based chemotherapy versus chemotherapy as first line treatment for patients with locally advanced or metastatic UC. Patients were randomized 1:1:1 to pembrolizumab and chemotherapy (n=351) or pembrolizumab alone (n= 307) or chemotherapy alone (n=352).
Rationale: 
The current standard for first line treatment in advanced UC is cisplatin-based chemotherapy. Pembrolizumab is recommended for patients as second line therapy or as first line therapy in patients that are PDL-1 positive and ineligible for platinum. Avelumab is recommended as maintenance treatment for patients who do not progress on first line chemotherapy.
Endpoints: 
There were dual primary endpoints, progression free survival (PFS) per RECIST by blinded independent review and overall survival (OS).
Comments: 
The results of this trial were unexpected as pembrolizumab is approved for metastatic disease as well as BCG unresponsive non-muscle invasive bladder cancer. The results seem to close the door for combination chemotherapy and immunotherapy in the front-line setting. In a somewhat similar study with atezolizumab, the combination led to improvement in PFS, but OS has yet to be reported.
Results: 
The combination of immunotherapy and chemotherapy did not reach statistical significance for PFS or OS in patients with untreated locally advanced or metastatic UC.

A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection

Status: 
Open
Sponsor: 
National Cancer Institute/Canadian Cancer Trials Group and Southwest Oncology Group
Enrollment: 
202
Study Design: 
This is a single-arm Phase II trial in which patients with BCG-unresponsive high-grade non-muscle muscle invasive bladder cancer (CIS ± Ta/T1 OR Ta/T1) received one year of atezolizumab anti PDL-1 therapy intravenously every 3 weeks x 17 cycles. Patients were evaluated every 3 months with cystoscopy and cytology with a mandatory biopsy done at 6 months.
Rationale: 
Immunotherapy and in particular anti PD-1 and anti PD-L1 therapies have demonstrated efficacy in metastatic urothelial cancer and in muscle-invasive bladder cancer. Therefore, these drugs are now being evaluated alone or in combination with other agents in BCG-unresponsive non-muscle invasive bladder cancer. The PD1 inhibitor pembrolizumab was approved in January 2020 and this trial is the first reporting results of a PD-L1 inhibitor (atezolizumab) in this high risk patient population.
Endpoints: 
The primary endpoint of the trial was the pathological CR rate at 6 months in patients with BCG-unresponsive CIS determined by a mandatory biopsy. The secondary endpoints included: 18-month event-free survival in the Ta/T1 cohort, progression-free survival in all patients, cystectomy-free survival in all patients, bladder-cancer specific survival in all patients, and overall survival in all patients.
Comments: 
The trial is a herculean effort to treat non-muscle invasive bladder cancer with systemic immunotherapy. Unfortunately, the strict statistical criteria for closure of this trial led to its falling short of its primary endpoint as the expectation of novel therapies in this disease space should provide a higher 6-month CR rate in patients with CIS. However, the 42% 3-month CR noted was similar to that seen with pembrolizumab which has been FDA-approved although the duration of response for atezolizumab is still pending at this time.
Results: 
The trial launched in 2017 but had a required futility analysis after 25 eligible CIS patients reached the 6 month-endpoint. In order to proceed, at least 7 patients had to have a CR and only 5 patients actually achieved a CR, so the trial was closed to accrual. Ultimately, 172 patients at 68 centers were enrolled of which 128 were eligible: 74 CIS ± Ta/T1 and 54 Ta/T1 without CIS. The CR rate at 6 months in CIS patients was 27% which fell below the null hypothesis of 30%. Of note, the CR rate at 3 months was 42% but this was an unplanned secondary endpoint. Toxicity data is yet unavailable but at least 9 patients in the CIS ± Ta/T1 cohort encountered grade 3-5 AEs during the course of the trial.

Phase II Trial of Atezolizumab in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (SWOG 1605)

Status: 
Open
Sponsor: 
National Cancer Institute/Canadian Cancer Trials Group and Southwest Oncology Group
Enrollment: 
202
Study Design: 
This is a single-arm Phase II trial in which patients with BCG-unresponsive high-grade non-muscle muscle invasive bladder cancer (CIS ± Ta/T1 OR Ta/T1) received one year of atezolizumab anti PDL-1 therapy intravenously every 3 weeks x 17 cycles. Patients were evaluated every 3 months with cystoscopy and cytology with a mandatory biopsy done at 6 months.
Rationale: 
Immunotherapy and in particular anti PD-1 and anti PD-L1 therapies have demonstrated efficacy in metastatic urothelial cancer and in muscle-invasive bladder cancer. Therefore, these drugs are now being evaluated alone or in combination with other agents in BCG-unresponsive non-muscle invasive bladder cancer. The PD1 inhibitor pembrolizumab was approved in January 2020 and this trial is the first reporting results of a PD-L1 inhibitor (atezolizumab) in this high risk patient population.
Endpoints: 
The primary endpoint of the trial was the pathological CR rate at 6 months in patients with BCG-unresponsive CIS determined by a mandatory biopsy. The secondary endpoints included: 18-month event-free survival in the Ta/T1 cohort, progression-free survival in all patients, cystectomy-free survival in all patients, bladder-cancer specific survival in all patients, and overall survival in all patients.
Comments: 
The trial is a herculean effort to treat non-muscle invasive bladder cancer with systemic immunotherapy. Unfortunately, the strict statistical criteria for closure of this trial led to its falling short of its primary endpoint as the expectation of novel therapies in this disease space should provide a higher 6-month CR rate in patients with CIS. However, the 42% 3-month CR noted was similar to that seen with pembrolizumab which has been FDA-approved although the duration of response for atezolizumab is still pending at this time.
Results: 
The trial launched in 2017 but had a required futility analysis after 25 eligible CIS patients reached the 6 month-endpoint. In order to proceed, at least 7 patients had to have a CR and only 5 patients actually achieved a CR, so the trial was closed to accrual. Ultimately, 172 patients at 68 centers were enrolled of which 128 were eligible: 74 CIS ± Ta/T1 and 54 Ta/T1 without CIS. The CR rate at 6 months in CIS patients was 27% which fell below the null hypothesis of 30%. Of note, the CR rate at 3 months was 42% but this was an unplanned secondary endpoint. Toxicity data is yet unavailable but at least 9 patients in the CIS ± Ta/T1 cohort encountered grade 3-5 AEs during the course of the trial.

Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma: JAVELIN Bladder 100 phase III results

Status: 
Open
Sponsor: 
Merck and Pfizer Inc
Enrollment: 
700
Study Design: 
Patients with unresectable locally advanced or metastatic UC treated with Cisplatin + gemcitabine or Carboplatin + gemcitabine chemotherapy (4-6 cycles) and obtained a CR, PR, or SD that was maintained for 4-10 weeks were entered into the study. They were randomized (1:1) between IV Avelumab (anti PDL-1) given every 2 weeks or best supportive care.
Rationale: 
Platinum-based combination chemotherapy has remained the standard-of-care as first-line treatment for advanced urothelial carcinoma (UC). However, durations of progression-free survival (PFS) and overall survival (OS) are limited by chemotherapy resistance
Endpoints: 
The primary endpoint was overall survival. Primary analysis populations included all randomized patients and separately the PD-L1+ population. Secondary endpoints included PFS and objective response per RECIST 1.1, Safety and tolerability and patient reported outcomes.
Comments: 
This Late Breaking Abstract was presented at the ASCO plenary session. Switch maintenance avelumab significantly prolonged overall survival vs best supportive care alone in selected patients with UC whose disease had not progressed on first line platin based chemotherapy. These results are practice changing. Based on these results, this concept has already been approved by the FDA on June 30, 2020.
Results: 
Maintenance avelumab significantly prolonged overall survival compared to best supportive care alone. The overall survival at 1 year was 71.3% vs 58.4%, and median overall survival was 21.4 vs 14.3 months (HR 0.69; 95% CI, 0.56, 0.86; 1-sided P<0.001). Avelumab also significantly prolonged overall survival in the PD-L1+ population as the overall survival at 1 year was 79.1% vs 60.4% (HR 0.56; 95% CI, 0.40, 0.79; 1-sided P<0.001). Adverse events occurred in 98.0% of patients in the avelumab arm and 77.7% of patients in the best supportive care alone arm, including grade ≥3 events in 47.4% and 25.2%, respectively.

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