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 3 Multicenter Trial Evaluating the Efficacy and Safety of UGN-101 on Ablation of Upper Urinary Tract Urothelial Carcinoma (OLYMPUS Study)

Sponsor: 
UroGen Pharma Ltd
Enrollment: 
71
Study Design: 
This was a Phase III multicenter, single-arm study evaluating the efficacy, safety, and tolerability of UGN-101 in the treatment of low-grade, non-invasive upper tract urothelial cancer. Patients had to have at least one lesion measuring between 5 and 15 mm left in place prior to treatment on this trial. Patients were treated by six weekly instillations of UGN-101 via a retrograde injection through a ureteral catheter and then evaluated 4-6 weeks after the last instillation.
Rationale: 
Upper tract urothelial cancer is difficult to treat given its relative scarcity compared to bladder urothelial cancer and the difficulties in delivering effective instillation of treatment within the upper urinary tract. UGN-101 is a novel investigational formulation of mitomycin C (MMC) admixed with a reverse thermal hydrogel that can be instilled as a liquid but that solidifies into a gel at body temperature. This allows for longer exposure of the urinary tract to MMC. Therefore, UGN-101 is an attractive agent for upper tract urothelial cancer that is unresectable and at high risk of recurrence.
Endpoints: 
The primary endpoint was a complete response (CR) rate defined as the percent of patients who achieved CR at the primary disease evaluation (PDE) visit which occurred on average at 11 weeks following initiation of treatment. The PDE consisted of ureteroscopy with biopsy of any remaining tumor and urine cytology. Patients who achieved CR at PDE were then treated once monthly with a maintenance regimen of UGN-101 for up to an additional 11 months or first recurrence.
Comments: 
This trial is trailblazing as it represents the first phase III trial in upper tract urothelial cancer. Furthermore, it demonstrates the tumor-ablative capacity of UGN-101 especially in patients deemed to be unresectable endoscopically at the start of the trial. Although serious side effects were seen, the mean age of patients was approximately 71 years and the fatal events were not deemed to be related to UGN-101. Furthermore, the side effects of ureteral narrowing and stricture could also have been due to the natural history of the disease and so without a comparator control group, it is hard to know if an observation cohort would have had the same side effects or not.
Results: 
The trial successfully enrolled 71 patients. Forty-two (59%) of the patients achieved a CR at the PDE visit. Of the 71 patients, 34 (48%) were deemed to have unresectable disease by their treating urologist and 19 (56%) of these “unresectable” patients achieved CR at the PDE visit. At 6 months of follow-up, 85% of evaluable patients with unresectable disease and 89% overall remained disease-free. The most common treated-related adverse events (AEs) were urinary tract infections, ureteral narrowing, and ureteral stricture formation. However, most of these were characterized as mild and resolved on follow-up.

QUILT-3.032: A Multicenter Clinical Trial of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 in Patients With BCG Unresponsive High Grade Non-Muscle Invasive Bladder Cancer (NMIBC)

Status: 
Recruiting
Sponsor: 
Altor BioScience
Enrollment: 
160
Study Design: 
The Phase II single-arm multicenter trial targeted BCG unresponsive high grade NMIBC patients who refused radical cystectomy. Two cohorts were enrolled: cohort A included patients with CIS with or without Ta or T1 tumors while cohort B only had Ta and/or T1 disease. Patients were then treated with intravesical N-803 + BCG in an induction schedule of weekly treatments for 6 weeks. At 3 months, patients were re-evaluated by cystoscopy and biopsy and either treated with a second induction course or a 3-week maintenance course consisting of weekly treatments for 3 weeks. Maintenance courses continued at 6, 9, 12, and 18 months for eligible patients.
Rationale: 
N-803 (also known as ALT-803) is an IL-15 immunostimulatory protein complex (IL-15RαFc) that can promote activation and proliferation of NK (natural killer) cells and CD8+ T cells without recruiting regulatory T cells. It was initially evaluated in a phase Ib trial as an intravesical agent in combination with BCG (NCT02138734) for BCG-naïve patients. Remarkably, all patients on the trial remained disease-free at 24 months; however, as a single arm study, the responses could have been due to the BCG. Therefore, a randomized trial is underway in BCG-naïve patients. In preclinical experiments, the combination of N-803 and BCG reduced tumor burden and recruited cytotoxic T lymphocytes. This led to the combination of intravesical N-803 and BCG being evaluated in BCG unresponsive, high grade NMIBC. Initial findings of this study were just reported at the AUA annual meeting.
Endpoints: 
The primary endpoint was complete response (CR) rate of CIS at any time point in cohort A and the disease-free rate at 12 months in cohort B.
Comments: 
This trial is limited for many reasons mainly because this is an early analysis with accrual still ongoing and analysis being limited to few patients. Nevertheless, important takeaways from this interim analysis are that 1) CIS patients had a high CR rate (with some CRs as long as 12-18 months) and 2) patients with papillary only disease had a 77% 6-month disease-free survival rate. CIS is historically difficult to treat when unresponsive to BCG and so the high CR rate in cohort A is extremely encouraging. Furthermore, the use of intravesical N-803 in combination with BCG may emerge to be a less toxic, less cumbersome, and less costly approach to BCG unresponsive disease than systemic immunotherapies that are now under evaluation.
Results: 
62 patients have been enrolled to date on this trial with 35 patients with CIS (cohort A) and 27 patients with papillary tumor only (cohort B). In cohort A, of 18 evaluable patients, 16 (89%) have achieved CR. In cohort B, of 13 evaluable patients, 10 (77%) demonstrated no disease at their 3-month and 6-month assessment. Of the 8 patients evaluated beyond this time point, no recurrences have been noted. Three treatment-related adverse events (AEs) were reported (infection, anemia, and bacteremia) ranging grades 2-3. None of the patients experienced immune-related AEs.

An Open Label, Single Arm, Phase II, Multicenter Study of the Safety and Efficacy of CG0070 Oncolytic Vector Regimen in Patients With Non-Muscle Invasive Bladder Carcinoma Who Have Failed BCG Therapy and Refused Cystectomy

Status: 
Open
Sponsor: 
Cold Genesys, Inc
Enrollment: 
66
Study Design: 
The Phase II single-arm multicenter trial targeted BCG unresponsive high-grade NMIBC patients who refused radical cystectomy. In the reported trial, interim results were published in 45 patients treated on the trial with at least 6 months of follow-up.
Rationale: 
CG0070 is a replication-competent oncolytic adenovirus that selectively replicates in retinoblastoma (Rb) pathway-defective cells that are often present in bladder cancer. The adenovirus also contains a transgene for granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that can active the immune system. CG0070 works by 2 major mechanisms: 1) induction of tumor lysis by selective replication in Rb-deficient tumor cells and 2) local GM-CSF production that augments immunogenic cell death.
Endpoints: 
The primary endpoint was 6-month complete response (CR) rate defined by absence of disease on cystoscopy, cytology, and random biopsies.
Comments: 
This trial is limited for many reasons including small numbers of patients, an interim analysis, and no comparison a control group given the heterogeneity of this disease and the multiple pathologic cohorts. Nevertheless, important takeaways from this interim analysis are that 1) CIS tumor respond best to this therapy and 2) pure T1 patients should be followed closely and counseled extensively on the need for early cystectomy. Finally, with an explosion of clinical trials in BCG unresponsive high grade NMIBC, it is important to remember that there is a real, albeit low risk of progression to muscle invasion.
Results: 
The disease characteristics of the 45 patients consisted of 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, and 3 T1. The overall 6-month complete response (CR) rate was 47% for all patients. CR was highest in pure CIS patients at 58% and lowest in pure Ta/T1 patients at 33%. Of note, none of the 3 pure T1 patients had a CR at 6 months and one patient (with Ta and T1 disease) progressed to muscle invasion. The most common treatment-related adverse events (AEs) were bladder spasms (36%), hematuria (28%), and dysuria (25%). However, none of the patients experienced grade 4-5 AEs.

A Phase 2, Randomized, Open Label, Parallel Arm Study to Evaluate the Safety and Efficacy of rAd-IFN/Syn3 Following Intravesical Administration in Subjects With High Grade, BCG Refractory or Relapsed Superficial Bladder Cancer

Status: 
Completed
Sponsor: 
FKD Therapies Oy
Enrollment: 
40
Study Design: 
This was a Phase II multicenter study targeting BCG unresponsive high grade NMIBC patients and refused to undergo radical cystectomy were randomized to one of two different Instiladrin viral particle dosages for their disease. The patients received treatments every 3 months for a total of 4 treatments if they continued to respond to therapy without a recurrence.
Rationale: 
Instiladrin is a non-replicating recombinant adenovirus vector containing the human interferon alpha-2b gene. It is administered intravesically and serves as a gene transfer vector and is formulated with Syn3, a polyamide surfactant that enhances the adenoviral transduction of the bladder lining. This allows for more reliable viral transduction of the IFNα-2b gene and ultimately production of IFNα-2b in the bladder. IFNα-2b is believed to be a key early cytokine in the immune response initiated by BCG and Instiladrin allows for more reliable production of this cytokine.
Endpoints: 
The primary endpoint was freedom from high grade recurrence-free survival (RFS) at 12 months defined by negative bladder biopsies.
Comments: 
This trial is limited for many reasons including the small number of patients and the lack of a comparison control group given the heterogeneity of this disease and the multiple pathologic cohorts. Interestingly, the RFS was least in the pure CIS patients at 12 months which is unfortunate since CIS that no longer responds to BCG some is among the most difficult to treat.. Furthermore, without a comparison control group, it is unknown if the high RFS seen at 12 months in Ta or T1 disease was due to the Instiladrin or to the resection of disease. However, it was tolerable and the phase III trial has already been completed and so results are eagerly anticipated.
Results: 
The disease states of the 40 patients consisted of 21 pure CIS, 4 CIS + Ta, 5 CIS + T1, 4 Ta, and 6 T1. Overall, the 12-month high grade RFS was 35% and was comparable between the two groups that only differed in the number of viral particles received. RFS at 12 months was highest in Ta or T1 patients at 50% and lowest in pure CIS patients at 29%. On long-term follow-up, seven patients who recurred with disease on the trial died within a median of 16 months. Although none of the deaths was thought to be treatment-related, at least two of the deaths were due to disease progression. The most common treated-related adverse events (AEs) were urgency (40%), dysuria (40%), and fatigue (33%). However, none of the patients experienced grade 4-5 AEs.

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.

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.

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.

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.

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