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 III Randomised Trial of Peri-Operative Chemotherapy Versus Surveillance in Upper Tract Urothelial Cancer (POUT Study)2

Status: 
Closed
Sponsor: 
Institute of Cancer Research, United Kingdom
Enrollment: 
261
Study Design: 
This was a phase III, multi-center open-label randomized controlled trial in which patients who had undergone nephroureterectomy for UTUC, with pT2-T4, N0 disease or pTany N1-3 M0 disease, and fit for adjuvant chemotherapy, were randomized (1:1) to either four cycles of platinum-based adjuvant chemotherapy or surveillance. Patients with microscopically positive margins on pathology were permitted as long as all gross disease was resected. Chemotherapy consisted of four 21-day cycles of gemcitabine-cisplatin, however, in patients with GFR 30-49 mL/min, carboplatin was substituted for cisplatin and was initiated within 90 days of surgery.
Rationale: 
The benefit of peri-operative chemotherapy for urothelial cancer of the bladder is well established for neoadjuvant therapy and less so for adjuvant therapy due to the difficulties in accrual to many of these trials. Although UTUC is related to urothelial cancer of the bladder, the role of chemotherapy and the proper sequencing of surgery with chemotherapy in UTUC is largely unknown and frequently extrapolated from the management of bladder cancer. This trial specifically evaluates the impact of adjuvant chemotherapy given after nephroureterectomy for high grade UTUC.
Endpoints: 
The primary endpoint of the trial was disease-free survival (DFS) at three years. The secondary endpoints included overall survival, metastasis-free survival, incidence of bladder second primary tumors, incidence of contralateral primary tumors, acute and late toxicity, treatment compliance, and quality of life.
Comments: 
Although renal function may be less optimal after nephroureterectomy, the rationale of adjuvant chemotherapy is that it would minimize overtreatment given more accurate staging with final pathology. However, many patients (estimated to be up to a third) will be ineligible for cisplatin-based adjuvant chemotherapy (GFR<50 mL/min) and subset analysis demonstrated no benefit with carboplatin-based chemotherapy. Nevertheless, this trial firmly establishes the benefit and role of adjuvant gemcitabine-cisplatin in patients with GFR>50 mL/min. This trial does not address neoadjuvant chemotherapy which conceivably would be more tolerable to patients (given better renal function with both kidneys in place) and demonstrates excellent overall survival from retrospective series. However, the risk of over-treatment of patients with neoadjuvant chemotherapy is significant given that chemotherapy is based on limited staging information obtained from ureteroscopic biopsies.
Results: 
Ultimately, 132 patients were assigned chemotherapy and 129 were assigned surveillance. Adjuvant chemotherapy significantly improved DFS (HR = 0.45, 95% CI 0.3-0.68, p=0.0001) at a median follow-up of 30.3 months with 3-year DFS estimates of 71% (chemotherapy) vs. 46% (surveillance). In addition, the metastasis-free survival rate at two years was 74% vs. 60% for chemotherapy vs. surveillance patients (p=0.002), respectively. However, overall survival was not significantly different between the groups in the early published analysis. On subset analysis, chemotherapy did not demonstrate a benefit in lymph node positive patients or patients with microscopic positive margins. Most importantly, subset analysis did not show a benefit with gemcitabine-carboplatin chemotherapy. Among all chemotherapy-treated patients, 44% had acute grade 3 or greater treatment-related adverse events (TRAEs). This is in comparison to a 4% acute grade 3 or greater TRAEs in the surveillance patients.

A Phase 3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ on Ablation of Upper Urinary Tract Urothelial Carcinoma (The OLYMPUS Study – Optimized DeLivery of Mitomycin for Primary Upper Tract Urothelial Carcinoma Study)1

Status: 
Closed
Sponsor: 
UroGen Pharma Ltd.
Enrollment: 
71
Study Design: 
This was a prospective, multicenter open-label single-arm trial evaluating the safety, efficacy, and tolerability of MitoGel instilled into the upper urinary tract of patients with non-invasive low-grade (LG) UTUC. Patients had to have at least one measurable papillary tumor. Patients were treated once weekly for 6 weeks by retrograde instillation. Safety and Efficacy was evaluated approximately 5 weeks following the last instillation, roughly 11 weeks after enrollment, by direct inspection of the upper tract, biopsies of any tumors, and upper tract washed urine cytology. Patients who achieved a CR at 3 months were treated with monthly maintenance therapy for a total of 11 instillations or up to the first recurrence whichever came first.
Rationale: 
Unlike bladder urothelial carcinoma, upper tract urothelial carcinoma (UTUC) has not been successfully treated with instillation therapy with chemotherapy or immunotherapy. Although some case reports describe instillation therapy into the upper urinary tract delivered through nephrostomy tubes, there has not been a reliable and convenient method of delivery until now. This trial uses a novel formulation of mitomycin C (MitoGel, now named JELMYTO) that can be instilled in a liquid form which can solidify at body temperature into a gel that can allow dwell times of several hours in the upper urinary tract. Mitomycin C is an alkylating agent that inhibits the transcription of DNA into RNA thereby preventing protein synthesis and inhibiting growth of cancer cells. It has shown to be effective in urothelial cancer of the bladder.
Endpoints: 
The primary endpoint was the complete response (CR) rate at 3 months. Secondary endpoints included the CR rate at 12 months. The mitomycin C level was also evaluated in the plasma of a subgroup of the patients.
Comments: 
This is the first trial exclusively for upper tract urothelial cancer and it establishes the first FDA-approved therapy in this rare, “orphan,” disease. In addition, the therapy was effective in patients without complete resection/ablation of existing papillary tumors. However, the response rate was only durable at 12 months in approximately 20% (14 of 71) of the patients and was limited to only those patients with LG disease. Given the inaccuracies with grading and staging of upper tract urothelial cancer based on small volume biopsies, it is also conceivable that some patients with high grade disease may be inadvertently treated with this approach which may not be effective. Nevertheless, this trial has paved the way for localized therapies for UTUC.
Results: 
This study demonstrated a CR rate of 59% (42 patients) at 3 months. Nineteen of these patients (46%) maintained a CR at 12 months. The most frequent adverse events included ureteric stenosis (44%), urinary tract infection (32%), hematuria (31%), flank pain (30%), and nausea (24%). Of note, of the patients who developed ureteric obstruction, 51% had some level of persistent obstruction.

A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection.

Sponsor: 
Hoffmann-La Roche
Enrollment: 
809
Study Design: 
This is a phase III, multicenter open-label trial that randomly assigned patients with muscle-invasive urothelial cancer after surgical resection with high risk features for recurrence to either observation or adjuvant atezolizumab treatment in a 1:1 fashion. Patients randomized to intravenous atezolizumab received therapy with 1200 mg every 3 weeks for up to 16 cycles. Patients with pT2-T4 disease after neoadjuvant chemotherapy, or pT3-4 disease without neoadjuvant chemotherapy, or any node positive disease after radical cystectomy were considered high risk for recurrence and eligible for the trial. Assessment of tumor status was performed by radiographic imaging prior to initiation of treatment.
Rationale: 
Patients with high-risk muscle invasive urothelial cancer after surgical resection have limited options for treatment. Historically, they have been observed only to later develop local or systemic recurrences and to eventually succumb to urothelial cancer. However, with the absence of a proven benefit of adjuvant therapy and dearth of treatments except for chemotherapy, there has been little progress in this disease space of urothelial cancer. This trial, also known as the IMvigor010 trial, aimed to evaluate the impact of adjuvant atezolizumab, a PD-L1 inhibitor, in patients randomized to receiving such therapy after radical cystectomy with high risk features seen on pathology.
Endpoints: 
Primary outcome was disease-free survival (DFS) from the time of randomization and included pelvic (local) recurrence, extravesical urinary tract recurrence, distant metastases, or death from any cause. Secondary outcomes included overall survival, disease-specific survival, disease metastasis-free survival, and non-urinary tract recurrence-free survival.
Comments: 
This trial unfortunately did not demonstrate a difference in DFS with the use of adjuvant atezolizumab. One of the criticisms is that this trial may have excluded patients likely to benefit and included patients unlikely to benefit with atezolizumab. Patients with positive surgical margins are most likely to recur with local (pelvic) recurrence and may benefit most from adjuvant therapy but were excluded from this trial. Another potential issue is potentially that there may be a difference in efficacy between PD-1 and PD-L1 inhibitors as PD-1 inhibitors have demonstrated slightly better survival results in some studies although no studies have directly compared these two different types of inhibitors.
Results: 
In this trial, Atezolizumab failed to meet the primary end point, disease-free survival (DFS), as adjuvant monotherapy in patients with muscle-invasive urothelial cancer (MIUC) compared with observation in the phase III IMvigor010 clinical trial, according to a press release from Roche, developer of the drug on January 24, 2020 (https://bit.ly/38zdRoE)

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: 
This is a phase II, multicenter trial for patients with high risk NMIBC (T1, CIS, and/or high-grade Ta) who are deemed BCG-unresponsive after adequate BCG therapy who are either unfit or refuse radical cystectomy. This was a single-arm study in which all patients were treated with intravenous pembrolizumab, 200 mg, every 3 weeks until recurrence of high-risk disease or unacceptable toxicity for up to 24 months. Assessment of tumor status was performed by cystoscopy and cytology and for cause biopsies every 3 months.
Rationale: 
PD-L1 and PD-1 inhibitors are now established treatments both for 1st line treatment of patients with locally advanced or metastatic bladder cancer that are cisplatin-ineligible or experiencing disease progression after platinum-based chemotherapy. Recently, data from 2 small phase II trials suggest their potential efficacy when given as neoadjuvant therapy prior to radical cystectomy. Several ongoing trials have also evaluated this immunotherapy in the treatment of BCG-unresponsive NMIBC. This trial by Merck Sharp & Dohme specifically evaluated the safety and efficacy of its PD-1 inhibitor, pembrolizumab, in the treatment of patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) given the already encouraging results in other disease states of urothelial cancer (neoadjuvant prior to cystectomy and metastatic).
Endpoints: 
Primary outcomes were complete response rate and disease-free survival rate. Complete response rate (CR) was defined by a negative cystoscopy or bladder biopsies performed for an abnormal cystoscopy, negative urine cytology, and normal CT urogram. Secondary outcome was duration of response.
Comments: 
This trial led to the approval of pembrolizumab in patients with BCG-unresponsive CIS. Although this is a valuable advance in the treatment of NMIBC, it does raise several potential concerns. Will this be used as first line therapy for patients with BCG unresponsive disease or will urologists choose alternative intravesical therapies such as gemcitabine/docetaxel. Two other intravesical therapies, vicinium and adenoviral mediated interferon mediated gene therapy, are currently under review by the FDA. The cost of immunotherapy will raise the cost of bladder cancer care astronomically imploring us to evaluate whether such treatment justifies the cost. This is especially sobering when one considers that on follow-up, only 19% of the entire cohort of CIS-treated patients continued with a CR of at least one year begging the question whether this is an appropriate benchmark for new therapies in the BCG-unresponsive disease state.
Results: 
At the time of analysis, the trial enrolled 148 patients of whom 96 patients had BCG-unresponsive CIS either with or without papillary tumors. The 3-month CR rate in the 96 patients with CIS was 41% (95% CI: 31-51) and the median duration of response was 16.2 months (range 0-30.4 months). Among the 39 patients with a CR, 18 (46%) and 19% among all patients with CIS maintained a CR of at least 12 months after starting treatment [Reference: fda.gov 1/8/2020]. The safety profile was in line with other PD-1 inhibitor studies, however, 99 patients experienced 1 or more adverse events (AEs) and treatment-related AEs were seen in up to 65.7% of patients. Although grade 3-5 AEs were only seen in 29.4% of patients, two patients died while on therapy during the course of the trial, but only one of these deaths was deemed to be immune-related.

IMvigor130: a phase III study of atezolizumab with or without platinum-based chemotherapy in previously untreated metastatic urothelial carcinoma (mUC)

Sponsor: 
Hoffmann-La Roche
Enrollment: 
1213
Study Design: 
IMvigor130 is an international phase III trial for pts with locally advanced or mUC who had not received prior systemic therapy. Pts had an ECOG PS ≤2 and were eligible for platinum-based therapy in the 1st line setting. Pts were stratified by PD-L1 IC status (IC0 vs IC1 vs IC2/3), Bajorin risk factor score including KPS <80% versus ≥80%, the presence of visceral metastases and investigator’s choice of chemotherapy. Pts were randomized 1:1:1 to receive atezo and platinum-based therapy (cisplatin or carboplatin) plus gemcitabine (arm A; n = 451), atezo monotherapy (arm B; n = 362), or placebo plus platinum-based therapy and gemcitabine (arm C; n = 400).
Rationale: 
Cisplatin-based chemotherapy has been standard first (1st) line treatment in mUC for > 30 years. Approximately 50% of patients (pts) with mUC are ineligible for cisplatin, and they generally receive inferior carboplatin-based regimens. PD-L1 and PD-1 inhibitors are the 1st new systemic therapies for mUC, both for 1st line treatment of cisplatin-ineligible pts and for pts experiencing disease progression despite platinum-based chemotherapy. The final PFS and interim OS results for IMvigor130, assessing atezolizumab (atezo) alone or in combination with gemcitabine and carboplatin or gemcitabine and cisplatin in 1st line mUC were presented.
Endpoints: 
The co-primary endpoints were investigator-assessed PFS and OS in arm A vs. arm C, and OS in arm B vs. arm C using a hierarchical approach. Key secondary endpoints included investigator-assessed overall response rate (ORR), duration of response, PFS and OS in arm B vs. arm C in the PD-L1 IC2/3 subgroup, and safety.
Comments: 
Whether the addition of immunotherapy to chemotherapy can improve outcomes in pts with mUC is an important question. IMvigor130 is the first trial to evaluate the combination of immunotherapy and chemotherapy in pts with mUC who are eligible and ineligible for chemotherapy. This trial represents the first positive signal in terms of PFS and a trend in OS. The results from IMvigor130 support atezo + platinum plus gemcitabine as an important new treatment option for patients with untreated mUC. Other similar trials are ongoing with other immunotherapeutic check point inhibitors.
Results: 
In the intent-to-treat population, the median OS with atezo and platinum plus gemcitabine was 16 months versus and 13.4 months for chemotherapy and placebo (HR, 0.83 (95% CI, 0.69, 1.00). When stratified by PD-L1 expression, pts with PD-L1–positive tumors (IC2/3) had an improvement in OS when treated with single-agent atezo compared with chemotherapy and placebo (HR, 0.68; 95% CI, 0.43-1.08). Median OS with the PD-L1 inhibitor was not estimated and was 17.8 mos. with chemotherapy. Follow-up of OS will be continued.

EV-103: Initial results of Enfortumab Vedotin plus Pembrolizumab for locally advanced or metastatic urothelial carcinoma (mUC)

Sponsor: 
Astellas Pharma Inc, in collaboration with Seattle Genetics
Enrollment: 
45
Study Design: 
This study examined the safety and anticancer activity of EV IV as monotherapy and in combination with other anticancer therapies in UC. The study will be conducted in multiple parts: dose escalation (enfortumab vedotin + pembrolizumab) and dose expansion (cohorts of enfortumab vedotin + pembrolizumab and/or chemotherapy) for locally advanced and metastatic UC and EV alone and in combination with pembrolizumab in patients with earlier stage of the disease (muscle invasive UC).
Rationale: 
There is a major unmet medical need for patients with mUC for whom available therapies have failed the patients. Antibody-drug conjugates (ADCs) are monoclonal Abs conjugated to cytotoxic drugs or a radionucleotide. This improves the potency and effectiveness of mAbs, allows for targeted delivery of a toxic payload to tumor cells, thereby minimizing non-specific, systemic toxicity. Enfortumab Vedotin (EV) is an ADC (anti-nectin 4 monoclonal Ab) linked to monomethyl auristatin E (MMAE) with evidence of induction of immunogenic cell death (ICD) in pre-clinical and in vitro data. MMAE disrupts microtubules resulting in ICD. EV showed an ORR of 45% in pts with prior PD-1/L1 inhibitors in a phase 1 study. In a single arm phase II trial (EV-201), single agent EV in pts previously treated with platinum and immune checkpoint inhibitors (NCT03219333) produced a 44% RR (12% CR; 32% PR) in 125 pts. The rationale for combining EV and an immune check point inhibitor such as pembrolizumab (pembro) stems from the fact that ICD releases innate immune activating molecules resulting in APC activation and presentation of tumor antigens to T cells. T cells mount antigen – specific response potentially augmented by PD-1/L1 inhibitors.
Endpoints: 
The primary goal of the study is to determine the safety, tolerability, and efficacy of EV alone and in combination with pembro and/or chemotherapy
Comments: 
EV alone had a high RR, but this study demonstrated that the combination of EV and immunotherapy with pembro has an even higher RR and is likely to become an important option in the first line setting for cisplatin ineligible pts in the treatment of mUC.
Results: 
EV and pembro in cisplatin ineligible 1st line or second line therapy results were reported in 45 pts. The ORR was 71% with 13% CR and 58% PR with rapid responses in 91% at first assessment.

Initial Results From TROPHY-U-01: A Phase 2 Open-Label Study of Sacituzumab Govitecan in Patients with Metastatic Urothelial Cancer (mUC) After Failure of Platinum-Based Regimens or Immunotherapy

Sponsor: 
Immunomedics, Inc
Enrollment: 
100
Study Design: 
TROPHY-U-01. SG 10 mg/kg was given on days 1 and 8 every 21 days. Data on Cohort A in 35 of 100 pts with mUC who progressed after prior platinum-based and checkpoint inhibition was presented.
Rationale: 
Pts who progress after platinum-based therapy or who don’t respond or don’t tolerate immunotherapy have limited treatment options and poor outcomes. Unfortunately, checkpoint inhibitors are ineffective for a majority of pts. Additional treatment options are needed. Sacituzumab Govitecan (SG) is a Trop-2-Directed Antibody-Drug Conjugate (ADC). Trop-2 is an epithelial cell surface antigen highly expressed in UC and a wide range of epithelial cancers. SG is distinct from other ADCs, with a high drug-to-antibody ratio. Linker hydrolysis releases the cytotoxic SN-38 in tumor tissue (intracellularly and in the tumor microenvironment. The payload for SG is SN-38, a Topo1 inhibitor and more potent active metabolite of irinotecan.
Endpoints: 
The primary objective was overall response rate (ORR). Secondary objectives included. safety/tolerability, duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
Comments: 
Antibody-Drug Conjugates are increasing of interest in the treatment of mUC. These data demonstrate that SG has the potential to change the treatment landscape of mUC.
Results: 
35 pts included in the interim analysis received ≥1 cycle of study treatment and had ≥1 on-treatment response assessment. The ORR was 29% (2 CR, 6 PR, 2 additional PRs pending confirmation). ORR was 25.0% in pts with liver metastases. 74% of pts demonstrated a reduction in tumor size at a median follow-up of 4.1 mos. 57% of pts are continuing treatment. SG was well tolerated, with a manageable, predictable, and consistent safety profile, with neutropenia and leukopenia as the main toxicities. Diarrhea and fatigue were observed.

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.

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