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

A Phase I Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination with Tremelimumab (Anti-CTLA-4 Antibody) in Subjects with Advanced Solid Tumors

Sponsor: 
Medimmune LLC
Enrollment: 
380
Study Design: 
This is a phase I combination study of durvalumab and tremelimumab for patients with metastatic urothelial cancer that has progressed after 1-2 prior treatments (including cisplatinum). Patients were treated with 4 cycles of concurrent durvalumab and tremelimumab and then treated with durvalumab alone for the remainder of the year.
Rationale: 
Anti-PD-(L)-1 antibody therapy has activity and approval as a post-platinum therapy for locally advanced and metastatic urothelial cancer. Anti-CTLA-4 agents are approved as second line therapy for urothelial cancers and may have synergistic activity with anti-PD-(L)-1 antibodies. This trial explores the safety and efficacy of the combination of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) in the metastatic urothelial cancer cohort of the dose-expansion phase for this phase I study of patients with advanced solid tumors.
Endpoints: 
Overall response rate, progression-free survival, overall survival
Comments: 
This trial demonstrates that combination therapy has manageable toxicity. Although efficacy was observed in all patients, it was better in those with 25% PD-L1 expression. Surprisingly, the addition of tremelimumab did not achieve response rates significantly higher than those seen in single agent anti-PD-(L)-1 trials begging the question, “do we really need to add an anti-CTLA4 antibody?”
Results: 
A total of 168 patients were analyzed. Overall treatment related adverse events were seen in 75.6% of patients. Pruritus, fatigue, diarrhea, and rash were the most common. However, grade 3 and 4 events were only seen in 28.6% and 0.6% suffered a grade 5 event. The overall response rate (complete and partial responses) was 20.8% for all patients. The response was 29.4% in patients with at least 25% or greater PD-L1 expression in tumor cells and immune cells. The median time to response was 1.8 months and median progression-free survival was 1.9 months. Median overall survival was 9.5 months in all patients. For patients who again had 25% PD-L1 expression, median survival was 18.9 months.

An Open Label, Single-arm, Phase 2 Study of Neoadjuvant Pembrolizumab (MK-3475) Before Cystectomy for Patients with Muscle-invasive Urothelial Bladder Cancer

Status: 
Recruiting
Sponsor: 
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Enrollment: 
90
Study Design: 
This is a Phase II, single arm clinical trial of patients with histologically confirmed MIBC (T2-T3bN0), predominant urothelial histology ( 50%), and residual disease after transurethral resection of bladder tumor. Although patients had to have GFR 20 mL/min, researchers were agnostic to cisplatin eligibility and patients were not offered cisplatin. Patients were treated with 3 treatments of 3 weekly treatments of pembrolizumab and then underwent radical cystectomy. Cystectomy specimens underwent genomic sequencing with the Foundation One Assay.
Rationale: 
Patients with muscle-invasive bladder cancer (MIBC) are at risk for relapse and poor overall survival due to understaging of disease and micrometastatic disease. Due to poor adoption of neoadjuvant chemotherapy and the lack of an effective non-cisplatin based regimen, this group from Italy sought to investigate the use of neoadjuvant pembrolizumab prior to radical cystectomy for MIBC.
Endpoints: 
In this interim analysis, the primary endpoint was pathologic complete response (pT0) rate and responses 25% were considered significant. Thirty-six patients were evaluated. The final trial will look at the 2-year overall survival rate in all planned 90 patients.
Comments: 
Overall, the results are very exciting and suggest that neoadjuvant pembrolizumab has activity in this setting and potential biomarkers associated with pT0 responses were identified. Although pT0 rates as high as almost 40% have been associated with neoadjuvant chemotherapy, a meta-analysis of 10 trials suggests that the pT0 rate from chemotherapy is closer to 27.8%.1 Also this trial required residual disease after transurethral resection of the bladder tumor and so the pT0 rate is even more impressive with pembrolizumab. Finally, the association of improved pT0 rates with DDR mutations, PD-L1 expression, and Rb1 mutations foretells a future where we may be able to more intelligently select patients for neoadjuvant therapies. However, there are some concerns with the trial. Four patients on the trial suffered unique complications such as ileal anastomosis dehiscence/fistula or ureteral anastomosis dehiscence. This raises a concern about the nature of potential surgical complications if completing immunotherapy 2-3 weeks before surgery. Nevertheless, this is a novel trial and will probably open the door for a randomized neoadjuvant trial of immunotherapy versus chemotherapy prior to radical cystectomy.
Results: 
Interim efficacy and an interim biomarker analysis was presented at the AACR meeting. The pT0 rate was 38.9% in all patients (47.4% in those with high PD-L1 expression defined as a combined positive score 23% which measures expression in tumor cells, lymphocytes, and macrophages). The pT0 rate was 60% in those with DNA Damage Repair (DDR) mutations and 100% in those with DDR mutations AND high PD-L1 expression. Mutational analysis demonstrated that Rb1 mutations were associated with pT0 response whereas FGFR3 mutations were associated with a non-pT0 response. Interestingly the median time from the end of pembrolizumab to radical cystectomy was 22 days and only 14 days in the last ten patients. Any grade adverse events were experienced in 47% patients but only 5.6% patients experienced grade 3-4 toxicity.

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.

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