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

A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab with or without Platinum-Based Combination Chemotherapy Versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial Carcinoma (KEYNOTE 361)

Sponsor: 
Merck Sharp & Dohme Corp.
Enrollment: 
990
Study Design: 
Similar to the above trial, this is a Phase III, 3-armed randomized clinical trial that includes both cisplatin eligible and ineligible patients with first line unresectable or metastatic stage IV urothelial cancer. The trial compares in a 1:1:1 randomization single agent. Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference laboratory, must be known prior to randomization.
Rationale: 
With the approvals of checkpoint inhibitors for urothelial cancer it has become of interest to assess the PD-1 checkpoint inhibitor, pembrolizumab, versus the combination of platin-based chemotherapy and a checkpoint inhibitor versus chemotherapy alone in the front line setting in both cisplatin eligible and ineligible patients. The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score [CPS] ≥10%) and in all participants (includes those participants with PD-L1 positive tumors and those with PD-L1 negative tumors [CPS <10%]).
Endpoints: 
PFS and OS
Comments: 
Pembrolizumab has approval in the first-line setting in patients with cisplatin-ineligible advanced/metastatic urothelial carcinoma based on the Phase 2 KEYNOTE 052 trial (5,6). In this study, durable responses were seen with objective responses in 106/370 (29%) patients, including complete responses in 25 (7%). The median duration of response was not reached after a median follow-up of 8 months. In the Phase 3 KEYNOTE-045 study, in the second-line setting, for patients with platinum-resistant/refractory disease, survival was superior to investigator's choice of chemotherapy at a median follow-up of 22.5 months (7).

Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma (IMvigor130)

Sponsor: 
Hoffmann-La Roche
Enrollment: 
1200
Study Design: 
This is a Phase III, 3-armed randomized clinical trial that includes both cisplatin eligible and ineligible patients with locally advanced or metastatic urothelial cancer and ECOG performance status < 2. The trial compares in a 1:1:1 randomization single agent atezolizumab alone to platinum-based combination chemotherapy with gemcitabine and cisplatin or carboplatin plus atezolizumab versus chemotherapy alone with gemcitabine and cisplatin or carboplatin and placebo.
Rationale: 
With the approvals of checkpoint inhibitors for urothelial cancer it has become of interest to assess the PD-L1 checkpoint inhibitor, atezolizumab, versus the combination of platin-based chemotherapy and a checkpoint inhibitor versus chemotherapy alone in the front line setting in both cisplatin eligible and ineligible patients.
Endpoints: 
PFS, OS and safety
Comments: 
This trial follows on the heels of the successful Phase II IMvigor 210 trial with atezolizumab in the first line setting in cisplatin ineligible patients (cohort 1) and IMvigor 210 (cohort 2) in patients who had failed prior platinum based chemotherapy (1-3). IMvigor 211, the phase III study in second line compared to chemotherapy did not meet its primary endpoint of an improvement in overall survival, in part due to the design of the study which relied heavily on PD-L1 status (4).

A Study of Atezolizumab in Participants with Locally Advanced or Metastatic Urothelial Bladder Cancer (Cohort 2)

Sponsor: 
Hoffman-La Roche
Study Design: 
The IMvigor210 study demonstrated safety and efficacy of atezolizumab in metastatic UC patients. This study looked at the outcomes of 220 patients (out of 310 total in cohort 2 of the study) who developed PD after therapy. Interestingly, 137 of these patients continued on atezolizumab post-PD compared with 83 patients who either received no systemic therapy (64 patients) or other systemic therapy (19 patients).
Rationale: 
The abstract presented at ESMO evaluated the outcomes of post-progressive disease (PD) in patients treated on the phase II IMvigor210 study.
Comments: 
This study suggests that patients may continue to derive benefit from atezolizumab even in the setting of progressive disease. Unfortunately, only 19 patients received alternate therapies after PD and so it would be difficult from this study to ascertain if other therapies might be more effective in the post-PD setting.
Results: 
The duration of pre-PD therapy was similar in both groups of patients and the patients continuing atezolizumab after PD had higher pre-PD ORR compared to the other patients. Interestingly, median OS was better in the group that continued atezolizumb after PD versus the patients that did not (12.8 months vs. 3.6 months). Furthermore, 45 patients in the atezolizumab continuation group experienced decreases in the sum of their target lesion diameters.

A Study of Nivolumab in Participants with Metastatic or Unresectable Bladder Cancer.

Sponsor: 
Bristol-Myers Squibb
Study Design: 
In the single-arm phase II Checkmate 275 study, patients with metastatic or surgically unresectable UC were treated with nivolumab. Of the 270 patients, 139 (51%) had evaluable TMB ascertained from tumor DNA from pre-treatment archival tumor tissue and matched whole blood samples. TMB was defined by the total number of missense somatic mutations per tumor. In this abstract, the association between TMB and PFS, ORR, and OS was investigated.
Rationale: 
The abstract presented at ESMO evaluated the impact of tumor mutation burden (TMB) on nivolumab’s efficacy (PD-1 inhibitor) from the previously conducted Checkmate 275 study.
Comments: 
This study suggests that TMB might enrich for responses to nivolumab that may be independent of PD-L1 expression.
Results: 
TMB demonstrated a statistically significant positive association with PFS (p=0.005) and ORR (p=0.002) but a statistically insignificant association with OS (p=0.067) even when adjusted for baseline tumor PD-L1 expression. In fact, patients with TMB had high ORR even with low (<1%) PD-L1 expression.

A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants with Urothelial Cancer (RANGE)

Sponsor: 
Eli Lilly and Company
Enrollment: 
530
Study Design: 
This is a Phase III, randomized double-blind, clinical trial comparing docetaxel to docetaxel and RAM in patients with progressive advanced or metastatic UC after platinum-based chemotherapy with the primary endpoint being PFS. Secondary endpoints included OS and objective response rate (ORR). Of note, patients were allowed to have received previous immune checkpoint inhibitor treatment.
Rationale: 
Again, given the limited options for platinum-refractory advanced or metastatic UC, this phase III trial evaluates the addition of ramucirumab (RAM) to docetaxel in these patients. Ramucirumab is a monoclonal antibody directed against VEGFR-2. In a previous phase II trial, the combination significantly improved median PFS over docetaxel alone.
Comments: 
This trial demonstrated the first statistically significant improvement in PFS in patients that have received previous platinum-based chemotherapy and possibly a previous immune-checkpoint inhibitor.
Results: 
Median PFS was slightly prolonged in the combination group compared to docetaxel plus placebo (4.1 vs. 2.8 months; HR 0.76, p=0.0118). The data were immature for OS determination but ORR was higher in the combination arm (24.5% vs. 14.0%). Finally, grade 3 adverse events were similar between the arms.

A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)

Sponsor: 
Merck
Enrollment: 
542
Study Design: 
This is a Phase III, randomized clinical trial comparing pembrolizumab for up to 2 years to chemotherapy in terms of OS and PFS. The chemotherapy regimen consists of either paclitaxel, docetaxel, or vinflunine and in a recent amendment, patients are able to crossover to receive pembrolizumab if they experience disease progression with chemotherapy. Eligibility is limited to patients with histologically confirmed UC with measurable disease after previous platinum therapy.
Rationale: 
Until recently, there were limited options for patients with locally advanced/unresectable urothelial cancer (UC) that has recurred or progressed after combination platinum-based chemotherapy. Given the activity of PD-1/PD-L1 inhibitors in the metastatic setting, this randomized trial aims to compare the impact of pembrolizumab on overall survival (OS) and progression-free survival (PFS) compared to chemotherapy (investigator’s choice of paclitaxel, docetaxel, or vinflunine). Previous Phase III results demonstrated longer OS in the pembrolizumab group and the updated results were presented at ESMO.
Comments: 
Additional follow-up confirms superior OS of pembrolizumab immunotherapy over chemotherapy as second-line treatment after cisplatin based combination chemotherapy.
Results: 
With median follow-up of 22.5 months for both treatment arms, median OS was significantly longer in the pembrolizumab arm in all patients (10.3 vs. 7.4 months; HR 0.70, p = 0.0003) which was an improvement over the earlier analysis with HR of 0.73. In patients with PD-L1 combined positive score (CPS; % of PD-L1 expressing tumor and inflammatory cells) 10%, median OS was also improved with pembrolizumab vs. chemotherapy (8.0 vs. 5.2 months; HR 0.58, p=0.003). The overall response rate was greater with pembrolizumab (21.1% vs. 11.0%) and treatment-related AEs of any grade were fewer (62.0% vs. 90.6%). However, PFS was not statistically different between the groups.

A Phase II Trial of MK3475 in Combination With Gemcitabine and Concurrent Hypofractionated Radiation Therapy as Bladder Sparing Treatment for Muscle-Invasive Urothelial Cancer of the Bladder

Status: 
Recruiting
Sponsor: 
New York University School of Medicine
Enrollment: 
54
Study Design: 
This is a single arm, Phase II study for muscle-invasive bladder cancer patients who are not cystectomy candidates or refuse cystectomy. Since the combination has not been evaluated together, there is a safety lead-in cohort of 3-6 patients.
Rationale: 
Building on the success of chemoradiotherapy for muscle-invasive bladder cancer and immunotherapy in bladder cancer, this trial combines pembrolizumab with gemcitabine and radiation therapy for muscle-invasive bladder cancer. The hypothesis is that the addition of a checkpoint inhibitor can achieve better local and systemic control of disease.
Endpoints: 
The primary endpoint is the two-year bladder-intact disease-free survival rate. This is freedom from bladder recurrence, pelvic recurrence, distant metastases, bladder cancer-related death, and cystectomy. Secondary endpoints include the following: safety, complete response rate, overall survival, and metastasis-free survival.
Comments: 
This trial expands on traditional inclusion criteria for chemoradiotherapy by allowing up to T4a tumors to be included and there is no exclusion criteria for associated CIS or hydronephrosis. This is concerning as we know from radiation literature that patients with these adverse pathologic features do not respond as well to chemoradiotherapy. Finally, a complete TURBT is not required for inclusion and this is most concerning as the radical TUR may be a critical part of the bladder-sparing approach. Perhaps the addition of immunotherapy can compensate for these adverse features and possibly expand the role of chemoradiotherapy.

A Phase II Protocol for Patients With Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemotherapy Following a Thorough Transurethral Surgical Re-Staging

Status: 
Recruiting
Sponsor: 
Radiation Therapy Oncology Group (RTOG)
Enrollment: 
37
Study Design: 
This is a single arm study treating patients with TURBT and then concurrent radiation therapy and chemotherapy. The chemotherapy regimen consists of either cisplatin or mitomycin plus fluorouracil, similar to that used by the MRC for locally advanced bladder cancer [1]. Eligibility is limited to patients with recurrent Ta or T1 high grade tumor after BCG therapy or patients in whom BCG is contra-indicated or patients that refuse BCG therapy. [1] James ND et al N Engl J Med (2012) Apr 19;366: (16):1477–88.
Rationale: 
Radiation combined with radiation-sensitizing chemotherapy has been effective in well-selected muscle-invasive bladder cancer patients. However, options for T1 bladder cancer refractory to BCG are limited and include radical cystectomy or experimental therapies. This trial applies trimodal therapy to T1 bladder cancer patients in the hope of sparing their bladders and effectively treating their disease.
Endpoints: 
The primary endpoint is the rate of freedom from radical cystectomy at 3 years. Secondary endpoints include: rate of freedom from radical cystectomy at 5 years, rate of freedom from the development of distant disease progression at 3 and 5 years, rate of freedom from progression of bladder tumor to stage T2 or greater at 3 and 5 years, disease-specific survival, overall survival, incidence of acute and late pelvic toxicity, recurrence of any local bladder tumor, potential prognostic value of tumor histopathology, molecular genetics, DNA content, and urine proteomics and the American Urological Association symptom scores at baseline and at 3 years.
Comments: 
BCG-refractory T1 bladder cancer can be quite aggressive and normally these patients are counseled to undergo radical cystectomy. This clinical trial presents a bladder-sparing option to these patients. This trial is nearing the end of its accrual and the results may establish a new standard of therapy. However, patient selection will be key as it is for chemoradiotherapy for muscle-invasive disease and patients without hydronephrosis, CIS, or variant histology are excluded from this trial. Importantly, patients require a radical and complete TUR for inclusion into this trial.

S1602, A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming With Intradermal BCG Before Intravesical Therapy for BCG-Naive High-Grade Non-muscle Invasive Bladder Cancer

Sponsor: 
Southwest Oncology Group (SWOG)
Enrollment: 
969
Study Design: 
S1602 also known as the “PRIME” study is a three-arm, phase III trial that will compare the effect of BCG strains (Tokyo vs TICE) and the effect of intradermal priming before intravesical instillation in patients with BCG-naïve high-grade non-muscle invasive bladder cancer. Eligible patients will be randomized to either standard intravesical TICE strain BCG or Tokyo-172 strain BCG or priming (intradermal Tokyo-172) followed by intravesical Tokyo-172 BCG. The accrual goal is 969 patients (323 patients per arm).
Rationale: 
Pre-existing immunity as suggested by a positive purified protein derivative (PPD) test is associated with a higher recurrence-free survival rate after BCG therapy in both patients and pre-clinical murine models. Furthermore, initial reports of BCG therapy in bladder cancer by Morales et al described subcutaneous BCG vaccination of patients concurrent with intravesical BCG. However, patients today are no longer treated with intradermal BCG vaccination at the time of intravesical instillation and are often treated without regard to their PPD status. Therefore, this trial evaluates whether intradermal priming 3 weeks before intravesical BCG instillation improves outcomes at one year compared to intravesical BCG instillation without priming. In addition, given the recent shortage of TICE and Connaught BCG strains and the announcement that Sanofi will no longer manufacture the BCG TICE strain, this trial evaluates treatment response with the Tokyo BCG strain as well.
Endpoints: 
The primary endpoint is time to high-grade recurrence. The secondary endpoint is disease-free rates at 6 months.
Comments: 
The primary objectives are: (1) to demonstrate non-inferiority of Tokyo-172 BCG strain compared to TICE and (2) to test the hypothesis that intravesical Tokyo-172 BCG with priming is superior to intravesical Tokyo-172 BCG without priming. All groups will undergo BCG induction followed by maintenance therapy as per the SWOG protocol. This trial is aimed at BCG-naïve patients and therefore it will be extremely important that each academic center reach out to local community urologists and encourage trial participation and/or patient referrals in order to successfully accrue the nearly 1000 patients required for this trial as these are the urologists who routinely see BCG-naïve disease.

S1605, Phase II Trial of Atezolizumab in BCG-Unresponsive Non-muscle Invasive Bladder Cancer

Sponsor: 
National Cancer Institute/Southwest Oncology Group
Enrollment: 
148
Study Design: 
S1605 is a single arm, phase II registration trial testing atezolizumab (PD-L1 inhibitor) in BCG-unresponsive, high-risk non-muscle invasive bladder cancer (Ta/T1/Tis). Eligible patients will receive intravenous atezolizumab every 3 weeks for one year.
Rationale: 
There are no established 2nd line therapies other than radical cystectomy with urinary diversion for patients with high-risk non-muscle invasive bladder cancer that is unresponsive to BCG. Building on the track record of immunotherapy in this disease in the form of BCG, as well as preclinical drug testing in animal models and the clinical efficacy of checkpoint blockade in the metastatic setting, this protocol aims to test the efficacy of atezolizumab in BCG-unresponsive high risk NMIBC.
Endpoints: 
There are two primary endpoints: 1) the complete response rate at 6 months in patients with carcinoma in situ (CIS; with or without concomitant Ta/T1 tumors) and 2) the event-free survival rate at 18 months in the overall cohort. To the first endpoint, the trial aims to accrue at least 70 patients with CIS. Secondary endpoints include the following: bladder cancer-specific survival, cystectomy-free survival, event-free survival at 18 months in the Ta/T1 subset, incidence of adverse events, toxicity assessment, overall survival, and progression-free survival. Correlative endpoints include expression of PD-L1 status on tumor and immune cells and CD8 in tumor and normal cells by immunohistochemistry (IHC) and expression of immune signatures by RNA sequencing.
Comments: 
This trial moves checkpoint blockade therapy into the high-risk non-muscle invasive BCG unresponsive disease setting after demonstrating success in metastatic disease. These patients do have an option for radical cystectomy, which is likely curative and so patients must be appropriately counseled. However, most patients can be carefully screened for enrollment with imaging and strict criteria for previous BCG treatment and can likely be salvaged with surgery or trimodal therapy in the event of disease recurrence or progression. A potential concern is whether a systemically delivered therapy will have activity locally within the bladder and whether it will come at the cost of systemic toxicity.

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