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

Keynote 57: A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Subjects With High Risk Non-muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy

Status: 
Recruiting
Sponsor: 
Merck Sharp & Dohme Corp
Enrollment: 
260
Study Design: 
Eligible patients had high-risk NMIBC unresponsive to BCG who refuse or are ineligible for cystectomy. Patients with papillary disease were fully resected prior to therapy. There were two cohorts: A) carcinoma in situ (CIS) with or without high grade papillary disease and B) high grade papillary disease without CIS. Subjects received pembrolizumab every 3 weeks and had standard cystoscopy, cytology, and if indicated, biopsy every 12 weeks for 2 years followed by every 24 weeks for 2 years.
Rationale: 
High-risk (HR) non-muscle invasive bladder cancer (NMIBC) is defined as carcinoma in situ (CIS), T1 tumor and/or high grade Ta tumor. The CR rate from TURBT and intravesical BCG is approximately 70%, however, a significant percentage of patients with high risk disease experience a recurrence and progression risk is 30-40% over a 10-year period. This is a single arm open-label Phase II study of pembrolizumab (MK-3475) 200mg IV every 3 weeks in patients unresponsive to BCG who refuse or are ineligible for cystectomy. Due to some of the remarkable long lasting responses and rapid approval of PD-1/PD-L1 inhibitors in metastatic urothelial cancer, several trials are ongoing to evaluate the impact of these drugs in patients with BCG unresponsive high risk NMIBC. In the absence of novel therapy, these patients ultimately are treated with radical cystectomy which is a potentially morbid operation. Therefore, this trial is the first of many that are ongoing to look at the potential impact of checkpoint inhibitors in localized high-risk urothelial cancer.
Endpoints: 
Primary Endpoints: In Cohort A, complete response (defined as the absence of high risk NMIBC) up to 3 years is the primary endpoint. In Cohort B, disease-free survival up to 3 years is the primary endpoint. Secondary Endpoints: The duration of response in Cohort A (absence of any disease either high-risk or low-risk NMIBC) along with overall safety/tolerability.
Comments: 
In this trial there was a very low risk of “missing the window of opportunity” for radical cystectomy as no patients progressed to muscle invasive disease and the complications of radical cystectomy were not increased. Although this preliminary data is exciting and establishes safety and efficacy, it may fall short of the bar set by expert consensus suggesting that novel therapies with activity in CIS BCG unresponsive NMIBC should result in an initial 40-50% CR rate at 6 months with a more durable CR of 30% at 12 months. Furthermore, this finding raises several important questions in patients who achieve a CR such as how long should therapy be continued and can the cost be justified especially if treatment continues beyond 12 months? This interim analysis is of interest, but 12-month data are needed.
Results: 
At ESMO 2018, Dr. De Wit and colleagues presented a 38.8% complete response (CR) rate in 40/103 patients in Cohort A (CIS containing BCG unresponsive high risk NMIBC) at 3 months among 103 patients. The median time to CR was 12.4 weeks and 80% had a CR duration of greater than or equal to 6 months. However, 25% of patients experienced recurrent NMIBC after CR. No patient developed muscle-invasive or metastatic bladder cancer.

Nivolumab Alone or in Combination With Ipilimumab in Patients With Platinum-Pretreated Metastatic Urothelial Carcinoma, Including the Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Expansion From CheckMate 032

Sponsor: 
Bristol-Myers Squibb
Study Design: 
Open-label, multicenter, phase 1/2 study
Rationale: 
Immunotherapy has become the recommended treatment for patients with previously treated metastatic urothelial cancer. Preclinical and clinical data indicate that the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) can improve antitumor activity in advanced melanoma, NSCLC, and mRCC.
Endpoints: 
Primary endpoints were investigator-assessed confirmed ORR by RECIST v1.1 and duration of response. Secondary endpoints included PFS, OS and safety. Exploratory endpoint was ORR by PD-L1 expression status.
Comments: 
CheckMate 032 is a multicenter, phase 1/2 study and not a randomized trial and one cannot compare across studies. The study reproduces previously presented preliminary results. Selected toxicities were higher but do not preclude treatment. A 38% RR is encouraging. Follow up is not mature but long-term outcomes (tail on curve) may be important. PD-L1 positive tumors may benefit the most (58%). It is still uncertain whether PD-L1 is a good predictive biomarker, as it has been problematic. More detailed interrogation of tumors beyond just PD-L1 would be ideal. A phase III trial is needed and ongoing (CheckMate 901; NCT03036098)
Results: 
35 patients responded for a 38% RR with 6 CR and 29 PR. The overall response rate by the investigator in patients with baseline PD-L1 >1% status was 58.1% and 54.8% by independent review. PFS assessed by the investigator was 4.9 (2.7–6.6) months. Median OS was 15.3 (10.1–27.6) months. ORR was numerically higher in patients with „1% tumor PD-L1 treated with NIVO1IPI3 (58%), and efficacy was observed across PD-L1 expression levels in all treatment arms.

A Phase I/II Study of IMMU-132 (hRS7-SN38 Antibody Drug Conjugate) in Patients With Epithelial Cancers

Sponsor: 
Immunomedics, Inc
Enrollment: 
250
Study Design: 
The Phase I/II trial included an expansion cohort of 41 patients with metastatic urothelial cancer that progressed after one or more prior systemic therapies. Patients were treated until progression or unacceptable toxicity.
Rationale: 
Patients with advanced epithelial cancers, including metastatic urothelial cancer (mUC), have a poor prognosis and this phase I/II trial looks at the safety and efficacy of a novel antibody-drug conjugate, IMMU-132 (hRS7-SN38), also known as Sacituzumab Govitecan. The antibody, hRS7, is a humanized anti-Trop-2 monoclonal antibody attached to SN38 which is the active metabolite of irinotecan (CPT-11). The drug targets Trop-2 which is overexpressed in aggressive epithelial cancers including up to 83% of urothelial tumors and the conjugate binds to Trop-2 and delivers the active metabolite of a topoisomerase I inhibitor.
Endpoints: 
The primary endpoint was safety and antitumor efficacy was the secondary endpoint.
Comments: 
Similar to data presented at ASCO 2018 for another antibody-drug conjugate, enfortumab vedotin, this trial demonstrates that IMMU-132 (hRS7-SN38), Sacituzumab Govitecan, also has good activity in patients who have not only failed prior platinum chemotherapy but also in patients who have failed prior checkpoint inhibitor therapy. The ongoing trial will further establish its activity.
Results: 
This was a heavily pre-treated cohort as patients received a median of 3 prior therapies including prior platinum chemotherapy in up to 93% of patients. Furthermore, 34% of patients had received a checkpoint inhibitor (CPI). Overall, the treatment was highly tolerable with grade 3-4 neutropenia being the most commonly seen adverse event (AE) in 39%. The overall response rate (ORR) was 34% with 2 complete responses. The response rate was 29% in patients who had received a previous checkpoint inhibitor. The median overall survival was 16.1 months.

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)

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).

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.

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