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

Pout: A phase III randomized trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC)

Enrollment: 
345
Study Design: 
Patients with UTUC ≤90 days post NU were randomized (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly cross sectional imaging and cystoscopy for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4.
Rationale: 
The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027) addresses whether adjuvant chemotherapy improves disease free survival (DFS) for pts with histologically confirmed pT2-T4 N0-3 M0 UTUC.
Endpoints: 
DFS
Results: 
The results were presented at ASCO GU, J Clin Oncol; abstract 407 in February 2018. Between May 2012 & Sept 2017, 248 pts were recruited (123 surveillance; 125 chemotherapy) at 57 UK centers. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (as of 05/09/2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Patients had median age 69 years (range 36-88), 30% pT2, 65% pT3; 91% pN0; Grade ≥3 toxicities were reported in 60% chemotherapy pts & 24% surveillance pts. 47/123 (surveillance) & 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favor of chemotherapy (log-rank p = 0.0009). Two year DFS was 51% for surveillance (95% CI: 39, 61) and 70% for chemotherapy (95% CI: 58, 79). PFS favored chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p = 0.003).

A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4

Status: 
Recruiting
Sponsor: 
Astellas Pharma Global Development, Inc.
Enrollment: 
215
Study Design: 
This is a Phase I, single arm clinical trial of patients with mUC treated with 1 or more prior chemotherapy regimens or who were cisplatin-ineligible. In this analysis, patients with mUC treated at the recommended phase 2 dose (RP2D) were analyzed.
Rationale: 
Patients with metastatic urothelial cancer (mUC) have a poor prognosis despite the approval of several immunotherapy agents. Therefore, this trial evaluates the use of a novel antibody-drug conjugate, ASG-22CE also known as enfortumab vedotin, in mUC patients. The drug targets Nectin-4 which is overexpressed in urothelial tumors and the conjugate binds to Nectin-4 and delivers a microtubule disrupting toxin.
Endpoints: 
The primary endpoint was tolerability and antitumor efficacy was the secondary endpoint.
Comments: 
This trial presents a unique and novel therapy for mUC patients who have not only failed prior platinum chemotherapy but also has activity in patients who have failed prior checkpoint inhibitor therapy and even have liver metastases. The data are still not yet mature but the preliminary data presented at ASCO 2018 are intriguing.
Results: 
Data as of January 2018 was presented at this year’s ASCO meeting (Abstract #4504), 155 mUC patients accrued of whom 112 received ASG-22CE at the RP2D. This was a heavily pre-treated cohort with aggressive disease evidenced by the following: 81% of patients received prior platinum chemotherapy, 60% received two or more prior therapies for metastatic disease, and 29% of patients had liver metastases. Furthermore, 84 patients (75%) had received a checkpoint inhibitor. Overall, the treatment was highly tolerable with grade ≤2 fatigue being the most commonly seen adverse event (AE) in 50%. Four patients however did experience a fatal treatment-related AE including respiratory failure, urinary tract obstruction, diabetic ketoacidosis, and multi-organ failure. The overall response rate (ORR) was 33% with 3 complete responses and 34 partial responses. Response rates were 32% in patients previously treated with checkpoint inhibitor vs. 37% in checkpoint inhibitor-naïve patients. The median overall survival was 12.5 months.

A Phase 2, Open-Label, Single-Agent, Multicenter Study to Evaluate the Efficacy and Safety of INCB054828 in Subjects with Metastatic or Surgically Unresectable Urothelial Carcinoma Harboring FGF/FGFR Alterations

Status: 
Recruiting
Sponsor: 
Incyte
Enrollment: 
140
Study Design: 
Subjects must have a known FGF/FGFR alteration and have either: (a) failed at least 1 previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie, chemotherapy, immunotherapy), or (b) have not received chemotherapy for metastatic or surgically unresectable urothelial carcinoma due to poor ECOG performance or have insufficient renal function (ie, creatinine clearance < 60 mL/min or local guidelines).
Rationale: 
This is an open-label monotherapy study of INCB054828, a selective FGFR 1, 2, and 3 inhibitor, in subjects with metastatic or surgically unresectable urothelial carcinoma harboring FGF/FGFR alterations. Subjects will receive INCB054828 at a once-daily (QD) starting dose of 13.5 mg on a 2-weeks-on-therapy and 1-week-off-therapy schedule.
Endpoints: 
Primary endpoints: Objective response rate in subjects with FGFR3 mutations or fusions based on central genomics laboratory results (Cohort A). Response will be based on review of scans by a centralized radiological review committee. Secondary Endpoints: Objective response rate in all subjects with FGFR3 mutations or fusions and all other FGF/FGFR alterations (Cohorts A and B combined). Objective response rate in subjects with all other FGF/FGFR alterations (Cohort B). Progression-free survival (both cohorts). Duration of response (both cohorts). Overall survival (both cohorts). Safety.

An Efficacy and Safety Study of JNJ-42756493 in Participants With Urothelial Cancer

Status: 
Recruiting
Sponsor: 
Janssen Research & Development, LLC
Enrollment: 
210
Rationale: 
JNJ-42756493 (Erdafitinib) is a selective and potent orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor with activity in patients with solid tumors with alterations in the FGFR pathway including urothelial carcinoma, indicating the potential to be a new therapeutic option for these patients. Recent advances in genomic profiling of urothelial carcinomas have identified potential therapeutic molecular targets in 69% of tumors (The Cancer Genome Atlas Project Nature 2014). Of the molecular alterations identified, FGFR signaling in particular is altered in a high proportion of bladder tumors in both muscle invasive (15–20%) and non-invasive tumors (70–80%).
Results: 
The Phase 2 study BLC2001 presented at the 2018 ASCO Genitourinary Cancers Symposium showed an overall response rate of 42 percent in 59 patients with relapsed/refractory metastatic urothelial cancer whose tumors harbored actionable FGFR mutations (ASCO-GU abstract #411, ASCO abstract #4503) A Breakthrough Therapy Designation in March 2018 was granted by the US FDA based on data from this multicenter, open-label Phase 2 clinical trial evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer, whose tumors have certain fibroblast growth factor receptor (FGFR) genetic alterations.

A Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Participants With Advanced Urothelial Cancer and Selected Fibroblast Growth Factor Receptor (FGFR) Gene Aberrations

Status: 
Recruiting
Sponsor: 
Janssen Research & Development, LLC
Enrollment: 
631
Study Design: 
Participants will be screened based on Fibroblast Growth Factor Receptor Inhibitor Clinical Trial Assay (FGFRi CTA) to determine molecular eligibility and participants who meet molecular eligibility criteria will be enrolled. Cohort 1: Erdafitinib vs Vinflunine or Docetaxel Cohort 2: Erdafitinib vs. Pembrolizumab
Rationale: 
This trial will evaluate erdafitinib compared with chemotherapy or immunotherapy in patients with advanced urothelial cancer and FGFR gene aberrations. This is evaluating erdafitinib in the first line setting.
Endpoints: 
Primary Endpoint: Overall Survival (OS) Secondary Endpoints: Time Frame: Approximately up to 3 years ; Progression-free Survival (PFS), Overall Response Rate (ORR), Patient-Reported Health Status, Patient-Global Impression of Severity (PGIS) Score, the Visual Analog Scale (VAS) of the EQ-5D-5L, Utility Scale of the EQ-5D-5L, Duration of Response (DOR), Safety, Oral Clearance (CL/F) of Erdafitinib, AUC of Erdafitinib

Study of Rogaratinib (BAY1163877) vs Chemotherapy in Patients With FGFR (Fibroblast Growth Factor Receptor)-Positive Locally Advanced or Metastatic Urothelial Carcinoma (FORT-1)

Status: 
Recruiting
Sponsor: 
Bayer
Enrollment: 
400
Rationale: 
To compare rogaratinib (BAY1163877) with chemotherapy (docetaxel, paclitaxel or vinflunine) in terms of prolonging the Overall survival (OS) of patients with FGFR positive urothelial carcinoma. At randomization, patients will have locally advanced or metastatic urothelial carcinoma and have received at least one prior platinum-containing chemotherapy regimen. Only patients with FGFR1 or 3 positive tumors can be randomized into the study. Archival tumor tissue is adequate for testing of FGFR1 and 3 mRNA expressions, which will be determined centrally using an RNA in situ hybridization (RNA-ISH) test. Approximately 42 % of UC patients with locally advanced or metastatic UC are identified as FGFR-positive by the RNA-ISH cut-off applied.
Endpoints: 
Primary Endpoint: Overall Survival Secondary Endpoints: Time Frame: Up to 45 months; Progression-free survival (PFS), Objective response rate (ORR,) Disease-control rate (DCR), Duration of response (DOR), safety and tolerability
Comments: 
The FGFR inhibitor trials are all being conducted in patients with FGFR alterations and locally advanced UC and the preliminary data presented at ASCO in at least one inhibitor is very encouraging. It will be interesting to see how an FGFR inhibitor performs in the first line setting in patients with an alteration when compared to standard chemotherapy or immunotherapy. Upper tract urothelial cancer (UTUC)

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 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 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).

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