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

Study Title: Testing MK-3475 (Pembrolizumab) After Surgery for Localized Muscle-Invasive Bladder Cancer and Locally Advanced Urothelial Cancer (AMBASSADOR)

Status: 
Open
Sponsor: 
National Cancer Institute (NCI)
Enrollment: 
739
Study Design: 
Eligible patients for the trial have high-risk muscle-invasive bladder cancer or upper tract urothelial carcinoma (UTUC). They must have undergone a cystectomy or nephrectomy within 16 weeks, have pT2-4aNx or pTxN+ disease after having undergone neoadjuvant chemotherapy. Patients can have pT3-4Nx or pN+ disease post surgery with no chemotherapy. Patients are stratified by PD-L1 positivity, receipt of prior neoadjuvant chemotherapy, and pathologic stage pT2/3/4aN0 vs. pT4bNx or N1-3 disease. They are then randomized to receive 200mg of pembrolizumab every three weeks for 12 months or to observation. Healthcare-related quality of life outcomes will also be measured.
Rationale: 
As mentioned in the two adjuvant trials above, there is not enough clinical trial evidence supporting adjuvant therapy in high risk MIUC. Similar to the two trials described above, this trial aims to evaluate pembrolizumab, a PD-1 immune checkpoint inhibitor, approved as monotherapy for treatment of platinum-resistant metastatic UC and platinum ineligible patients as well as in NMIBC patient who have failed BCG, as adjuvant therapy in patients with high-risk MIUC.
Endpoints: 
The primary objectives of this study are to determine overall survival (OS) and DFS
Comments: 
It is hoped that this study will finish its accrual after presentation of the positive adjuvant Nivolumab trial.
Results: 
Still accruing

A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection (IMvigor010)

Status: 
Open
Sponsor: 
F Hoffmann-La Roche/Genentech
Enrollment: 
809
Study Design: 
IMvigor010 was a multicenter international open-label, randomized, phase 3 trial for patients after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumors following neoadjuvant chemotherapy or pT3-4a or pN+ tumors if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy were required to be cisplatin ineligible or declined cisplatin-based adjuvant chemotherapy. Patients were randomized (1:1) to atezolizumab anti PD-L1 immunotherapy IV every 3 weeks for 1 year vs. observation. Randomization was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumor stage, and PD-L1 expression on tumor-infiltrating immune cells.
Rationale: 
As mentioned earlier in the nivolumab aduvant trial, despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and there is not enough clincal trial evidence supporting adjuvant therapy. This trial aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk MIUC.
Endpoints: 
The primary endpoint was disease-free survival in the ITT population.
Comments: 
IMvigor010 was the first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in MIUC. The trial did not meet its primary endpoint of improved DFS in the atezolizumab group compared to observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant atezolizumab therapy in MIUC. The results differ from those in the nivolumab study. There were more patients who discontinued therapy in this study and the reasons for the differences between the two trials require further exploration.
Results: 
406 patients were assigned to the atezolizumab group and 403 were assigned to observation. Median follow-up was 21.9 months (IQR 13.2-29.8). Median DFS was 19.4 months (95% CI 15.9-24.8) with atezolizumab and 16.6 months (11.2-24.8) with observation (stratified hazard ratio 0.89 [95% CI 0.74-1.08]; p=0.24).

An Investigational Immuno-therapy Study of Nivolumab, Compared to Placebo, in Patients With Bladder or Upper Urinary Tract Cancer, Following Surgery to Remove the Cancer (CheckMate 274)

Status: 
Open
Sponsor: 
Bristol-Myers Squibb
Enrollment: 
709
Study Design: 
CheckMate 274 is a phase 3, randomized, double-blind, multicenter study of adjuvant nivolumab versus placebo in patients with high-risk MIUC. Inclusion criteria were: Patients with ypT2-ypT4a or ypN+ MIUC who had neoadjuvant cisplatin-based CT, or pT3-pT4a or pN+ MIUC without prior neoadjuvant cisplatin-based CT, and not eligible for or refused adjuvant cisplatin-based CT; radical surgery performed within the past 120 days and disease-free status within 4 weeks of dosing. Patients were randomized 1:1 to nivolumb IV 240 mg every 2 weeks vs. placebo IV every 2 weeks x 1 year. Stratification factors included: PD-L1 status (<1% vs ≥ 1%) , prior neoadjuvant cisplatin-based chemotherapy and nodal status.
Rationale: 
Radical surgical resection is the standard of care for patients with MIUC. Adjuvant therapy after radical surgery is not currently recommended for patients who have received neoadjuvant therapy... For patients who have not had neoadjuvant cisplatin-based CT, adjuvant cisplatin-based CT may be offered but the level of evidence is low. Nivolumab, a PD-1 immune checkpoint inhibitor, is approved as monotherapy for treatment of platinum-resistant metastatic UC. Until this trial , no immunotherapy has shown efficacy as adjuvant therapy in patients with MIUC at high risk for recurrence after radical surgery.
Endpoints: 
The primary endpoints were disease free survival in the intent to treat (ITT) population and DFS in all randomized patients with tumor PD-L1 ≥ 1%.
Comments: 
Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC. The FDA has granted priority review, although the overall survival data are not yet mature. These results may well support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery, irrespective of PD-L1 status and prior neoadjuvant chemotherapy. The results differ from what was found in the adjuvant atezolizumab trial highlighted below.
Results: 
Adjuvant nivolumab significantly improved DFS in patients with high-risk MIUC after radical surgery, both in the ITT and PD-L1 ≥ 1% populations. In the ITT population, the median DFS with nivolumab was 21.0 (17.1–33.4) months vs 10.9 (8.3–13.9) months, HR, 0.70 (98.31% CI, 0.54–0.89) in patients treated with placebo (p < 0.001). In the PD-L1 ≥ 1% population, median DFS was NR (22.0–NE) vs 10.8 (5.7–21.2) months, HR, 0.53 (98.87% CI, 0.34–0.84), respectively (p < 0.001). No deterioration in health related quality of life, as measured by change in EORTC QLQ-C30 global health status score, was observed with nivolumab vs placebo.

A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

Status: 
Open
Sponsor: 
Astellas Pharma Global Development
Enrollment: 
608
Study Design: 
This was an international open-label, phase 3 trial of enfortumab vedotin, an antibody drug conjugate that targets Nectin-4 and carries a Monomethyl Auristatin E (MMAE) Payload, a microtubule-disrupting agent, as compared to investigator’s chemotherapy of choice in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin or docetaxel, paclitaxel, or vinflunine.
Rationale: 
Patients with advanced urothelial carcinoma have poor overall survival when recurring after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment. More novel therapies are needed.
Endpoints: 
The primary end point was overall survival (OS).
Comments: 
The FDA approved enfortumab vedotin for treatment of patients with locally advanced or metastatic UC previously treated with a PD-(L)1 inhibitor and platinum-containing CT in the (neo)adjuvant, locally advanced, or metastatic setting. A second antibody drug conjugate Sacituzumab Govitecan, that targets Targets Trop-2, with a SN-38 Payload, the active metabolite of irinotecan, was also recently approved for locally advanced or metastatic UC previously treated with a PD-L1 inhibitor and either platinum ineligible or previously treated with platinum-containing CT in the (neo)adjuvant, locally advanced, or metastatic setting.
Results: 
301 patients were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. OS was longer in the enfortumab vedotin group than in the chemotherapy group (median 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival(PFS) was also longer in the enfortumab vedotin group than in the chemotherapy group (median 5.55 vs. 3.71 months; HR for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The study was halted by the IDMC at this analysis and it was recommended to the sponsor to allow crossover of patients on chemotherapy at PD to enfortumab vedotin.

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 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.

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 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.

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.

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