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: piyush.agarwal@nih.gov and/or cnsternberg@corasternberg.com.

Sincerely,

Piyush K. Agarwal Cora N. Sternberg
Piyush K. Agarwal, MD Cora N. Sternberg, MD, FACP
Associate Editor, Bladder Cancer Associate Editor, Bladder Cancer
Head, Bladder Cancer Section Chair, Department of Medical Oncology
Urologic Oncology Branch San Camillo Forlanini Hospital
National Cancer Institute Rome, Italy
Bethesda, MD, USA

Study of Nivolumab in Combination With Ipilimumab or Standard of Care Chemotherapy Compared to the Standard of Care Chemotherapy Alone in Treatment of Patients With Untreated Inoperable or Metastatic Urothelial Cancer (CheckMate901)

Sponsor: 
Bristol-Myers Squibb + Ono Pharmaceutical Co. Ltd
Enrollment: 
897
Study Design: 
This is a Phase III, 4-armed randomized parallel assessment clinical trial with experimental and comparator arms that includes both cisplatin eligible and ineligible patients with first line unresectable or metastatic urothelial cancer. The trial compares the combination of nivolumab and ipilumimab to nivolumab plus cisplatin and gemcitabine followed by nivolumab only versus gemcitabine and cisplatin or gemcitabine and carboplatin.
Rationale: 
The purpose of this study is to determine whether immunotherapy with a PD-1 inhibitor, Nivolumab, in combination with ipilimumab, a CTLA-4 inhibitor, or in combination with standard of care chemotherapy is more effective than standard of care chemotherapy alone in treating patients with previously untreated inoperable or metastatic urothelial cancer.
Endpoints: 
PFS and OS
Comments: 
Nivolumab has been evaluated in metastatic urothelial carcinoma after platinum therapy in the CheckMate 275 trial. This was a multicenter, single-arm, phase 2 trial in which 270 patients received nivolumab and 265 were evaluated for activity. Median follow-up for overall survival was 7 months. Confirmed objective response was achieved in 52 (19.6%) of 265 patients. Confirmed objective response was observed in 23 (28.4%) of 81 patients with PD-L1 expression > 5%, 29 (23.8%) of 122 patients with PD-L1 expression > 1%, and 23 (16.1%) of 143 patients with PD-L1 expression <1% PD-L1 expression. In this study, nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. The CTLA-4 inhibitor ipilimumab has clinical activity in melanoma as a single agent or in combination with the nivolumab, establishing the paradigm for exploring the combination in urothelial carcinoma (9). Additionally, some evidence has suggested that ipilimumab has biologic activity in urothelial cancer (10).

Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer

Sponsor: 
AstraZeneca
Enrollment: 
1005
Study Design: 
This is a Phase III, 3-armed randomized clinical trial that includes both cisplatin eligible and ineligible patients with first line metastatic urothelial cancer. The trial compares in a 1:1:1 randomization of single agent durvalumab to the combination of durvalumab and tremilumumab to platinum-based chemotherapy alone with gemcitabine in combination with either cisplatin or carboplatin. Patients will be treated with durvalumab or durvalumab with tremelimumab or treated with chemotherapy until progressive disease is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.
Rationale: 
Durvalumab is a fully human monoclonal antibody that blocks PDL-1 binding to its receptors PD-1 and CD80, resulting in enhanced T-cell responses against cancer cells. This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of durvalumab (MEDI4736) monotherapy and durvalumab in combination with tremelimumab, a CTLA-4 inhibitor versus gemcitabine and cisplatin or carboplatin as first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder and urethra). As in the two prior studies, and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines, both cisplatin and carboplatin are permitted.
Endpoints: 
OS of the combination of durvalumab with tremelimumab compared to standard of care chemotherapy and to assess the efficacy of durvalumab monotherapy versus standard of care chemotherapy in terms of OS in patients with unresectable Stage IV PD-L1- High urothelial cancer.
Comments: 
An ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic urothelial cancer whose disease had progressed on, were ineligible for, or refused prior chemotherapy was used to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma, resulting in its US FDA approval. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] post platinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were seen early with a median time to response of 1.41 months, durable (median duration of response not reached), and observed irrespective of PD-L1 expression. Durvalumab, given every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile (7). The combination of durvalumab with tremelimumab have been evaluated in other tumor types.

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 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 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 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 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 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.

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