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, 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

S1605, Phase II Trial of Atezolizumab in BCG-Unresponsive Non-muscle Invasive Bladder Cancer

Sponsor: 
National Cancer Institute/Southwest Oncology Group
Enrollment: 
148
Study Design: 
S1605 is a single arm, phase II registration trial testing atezolizumab (PD-L1 inhibitor) in BCG-unresponsive, high-risk non-muscle invasive bladder cancer (Ta/T1/Tis). Eligible patients will receive intravenous atezolizumab every 3 weeks for one year.
Rationale: 
There are no established 2nd line therapies other than radical cystectomy with urinary diversion for patients with high-risk non-muscle invasive bladder cancer that is unresponsive to BCG. Building on the track record of immunotherapy in this disease in the form of BCG, as well as preclinical drug testing in animal models and the clinical efficacy of checkpoint blockade in the metastatic setting, this protocol aims to test the efficacy of atezolizumab in BCG-unresponsive high risk NMIBC.
Endpoints: 
There are two primary endpoints: 1) the complete response rate at 6 months in patients with carcinoma in situ (CIS; with or without concomitant Ta/T1 tumors) and 2) the event-free survival rate at 18 months in the overall cohort. To the first endpoint, the trial aims to accrue at least 70 patients with CIS. Secondary endpoints include the following: bladder cancer-specific survival, cystectomy-free survival, event-free survival at 18 months in the Ta/T1 subset, incidence of adverse events, toxicity assessment, overall survival, and progression-free survival. Correlative endpoints include expression of PD-L1 status on tumor and immune cells and CD8 in tumor and normal cells by immunohistochemistry (IHC) and expression of immune signatures by RNA sequencing.
Comments: 
This trial moves checkpoint blockade therapy into the high-risk non-muscle invasive BCG unresponsive disease setting after demonstrating success in metastatic disease. These patients do have an option for radical cystectomy, which is likely curative and so patients must be appropriately counseled. However, most patients can be carefully screened for enrollment with imaging and strict criteria for previous BCG treatment and can likely be salvaged with surgery or trimodal therapy in the event of disease recurrence or progression. A potential concern is whether a systemically delivered therapy will have activity locally within the bladder and whether it will come at the cost of systemic toxicity.

S1602, A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming With Intradermal BCG Before Intravesical Therapy for BCG-Naive High-Grade Non-muscle Invasive Bladder Cancer

Sponsor: 
Southwest Oncology Group (SWOG)
Enrollment: 
969
Study Design: 
S1602 also known as the “PRIME” study is a three-arm, phase III trial that will compare the effect of BCG strains (Tokyo vs TICE) and the effect of intradermal priming before intravesical instillation in patients with BCG-naïve high-grade non-muscle invasive bladder cancer. Eligible patients will be randomized to either standard intravesical TICE strain BCG or Tokyo-172 strain BCG or priming (intradermal Tokyo-172) followed by intravesical Tokyo-172 BCG. The accrual goal is 969 patients (323 patients per arm).
Rationale: 
Pre-existing immunity as suggested by a positive purified protein derivative (PPD) test is associated with a higher recurrence-free survival rate after BCG therapy in both patients and pre-clinical murine models. Furthermore, initial reports of BCG therapy in bladder cancer by Morales et al described subcutaneous BCG vaccination of patients concurrent with intravesical BCG. However, patients today are no longer treated with intradermal BCG vaccination at the time of intravesical instillation and are often treated without regard to their PPD status. Therefore, this trial evaluates whether intradermal priming 3 weeks before intravesical BCG instillation improves outcomes at one year compared to intravesical BCG instillation without priming. In addition, given the recent shortage of TICE and Connaught BCG strains and the announcement that Sanofi will no longer manufacture the BCG TICE strain, this trial evaluates treatment response with the Tokyo BCG strain as well.
Endpoints: 
The primary endpoint is time to high-grade recurrence. The secondary endpoint is disease-free rates at 6 months.
Comments: 
The primary objectives are: (1) to demonstrate non-inferiority of Tokyo-172 BCG strain compared to TICE and (2) to test the hypothesis that intravesical Tokyo-172 BCG with priming is superior to intravesical Tokyo-172 BCG without priming. All groups will undergo BCG induction followed by maintenance therapy as per the SWOG protocol. This trial is aimed at BCG-naïve patients and therefore it will be extremely important that each academic center reach out to local community urologists and encourage trial participation and/or patient referrals in order to successfully accrue the nearly 1000 patients required for this trial as these are the urologists who routinely see BCG-naïve disease.

PDL-1 expression, the Cancer Genome Atlas (TCGA) Subtype and Mutational Load are independent predictors of response to atezolizumab in Metastatic Urothelial Carcinoma (mUC, IMvigor 210).

Status: 
Open
Sponsor: 
Hoffmann-La Roche
Enrollment: 
310
Study Design: 
Cohort 2 was a phase II study of patients who had received >1 platinum containing regimens. The results have been published (Rosenberg JE et al Lancet. 2016 May 7;387(10031):1909-20) leading to FDA approval of atezolizumab in metastatic urothelial cancer refractory to standard chemotherapy
Rationale: 
Immunologic correlates corresponding to the TCGA Subgroups were evaluated and updated at ASCO (Rosenberg JE et al).
Results: 
It was shown that PDL-1 status, TCGA subgroup (particularly the luminal subgroup) and mutational load were independently associated with response to atezolizumab. The luminal subgroup was associated with a more inflamed environment than the basal subtype. The luminal subtype was also found to have high Teff cells and low stromal gene expression. Assessment of these characteristics may define drivers of immune responses. Further work on the biology of immune response to checkpoint inhibits is clearly a priority.

A Phase 1/2 Study to Evaluate MEDI4736

Sponsor: 
MedImmune LLC
Enrollment: 
1014
Study Design: 
Phase I/II multicenter first in human study with standard 3+3 dose escalation in advanced solid tumors. The primary endpoint included safety and tolerability. The secondary endpoints include objective response rate, progression-free survival, overall survival, and PD-L1 expression on both tumor cells and tumor infiltrating immune cells.
Rationale: 
This is a first in human study of Medimmune’s PD-L1 inhibitor durvalumab (MEDI4736) focused on dose expansion in a urothelial bladder cancer cohort (Massard C et al).
Comments: 
Durvalumab had a reasonable safety profile and ORR was greater in the PD-L1+ group versus the PD-L1 negative group. Of note, each trial has used different definitions for PD-1/PD-L1 expression. Expression does appear to correlate with response with some tests but absolute numbers are variable across different agents and different studies. Phase III trials are ongoing with this agent in bladder cancer.
Results: 
61 bladder cancer patients were enrolled. Drug-related adverse events occurred in 64% and only 3 patients had ≥grade 3 adverse events. Objective response rate (ORR) was greater in patients with at least 25% or greater PD-L1 expression in either tumor cells or tumor infiltrating immune cells versus less than 25% expression in both (46% vs. 0% ). ORR was 46% in the PDL-1 subgroup vs 0% in the PDL-1 negative group. For the whole population, the RR was 31% . Median duration of follow-up was26 weeks.

Limited versus extended pelvic lymphadenectomy in patients with bladder cancer undergoing radical cystectomy: Survival results from a prospective randomized trial (LEA AUO AB 25/02).

Sponsor: 
Association of Urogenital Oncology (AUO)
Enrollment: 
400
Study Design: 
This is the first randomized surgical study in bladder cancer randomizing patients with pT2 or greater disease and without neoadjuvant chemotherapy to either a limited lymph node dissection or an extended lymph node dissection. The limited node dissection consisted of external iliac, internal iliac, and obturator lymph nodes while the extended lymph node dissection included these areas in addition to the deep obturator, presacral, interaortocaval, paracaval, and periaortic lymph nodes up to the inferior mesenteric artery. Patients with organ-confined disease and negative nodes were observed whereas patients with non-organ-confined disease and/or positive lymph nodes were offered adjuvant chemotherapy. The primary endpoint was 5-year recurrence-free survival (RFS). Secondary endpoints include complication rate, influence of adjuvant chemotherapy, disease-specific survival, overall survival, and local recurrences and distant metastases.
Rationale: 
The proximal extent of a lymph node dissection (LND) at the time of radical cystectomy has always been an issue of controversy. Some reports suggest that a dissection to the common iliac bifurcation or to the ureter crossing over the iliac vessels is adequate whereas others suggest that more proximal dissection to the inferior mesenteric artery may affect survival. Furthermore, removal of the presacral lymph nodes and the deep obturator lymph nodes are not routinely done by all surgeons.
Comments: 
Although there was a trend towards improved survival in the extended LND group, there was not a statistically significant difference. There are two factors likely for this as 1) the limited LND was still extensive in these patients as evidenced by a median lymph node removal count of 19 and 2) the magnitude of benefit was probably overestimated from an extended LND and the rate of recurrence in the limited LND was also overestimated. The benefit was seen in the organ-confined group on post-hoc analysis, however, no patients with neoadjuvant chemotherapy were included and perhaps this difference would have disappeared with the addition of neoadjuvant chemotherapy? However, adjuvant chemotherapy appeared have a statistically significant benefit even though its use was limited. It will be interesting to see the conclusions reached by the ongoing SWOG 1011 trial but this study failed to show a benefit based on its design.
Results: 
Ultimately 437 patients were randomized but 64 patients dropped out due to inclusion/exclusion violations leaving 190 patients in the limited LND group and 183 in the extended LND group by an intention to treat analysis. Median follow-up was about 33 months. The lymph node positive rate was 27.4% for the limited LND group and 20.2% for the extended LND group. Overall, the positive node rate was 23.9% among patients and approximately 14% of patients received adjuvant chemotherapy. The median lymph node removal was 19 for limited LND and 31 for extended LND, p < 0.01. The 5-year RFS was 61.5% for the limited LND and 67% for the extended LND, p = 0.34. Secondary endpoints were also not statistically significant including 5-year disease-specific survival, 5-year OS, and complication rate. On post-hoc analysis of organ-confined tumors (pT2), there was a survival benefit in 5-year RFS (62.5% vs. 85% , p = 0.01) and 5-year OS (59.1% vs. 79.8% , p = 0.04) favoring the extended LND group. In 89 patients with positive lymph nodes, adjuvant chemotherapy improved median RFS (35.9 months vs. 8.8 months, p = 0.0002).

A Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer [IMvigor210]

Status: 
Open
Sponsor: 
Hoffmann-La Roche
Primary Investigator(s): 
Study Director: Clinical Trials Hoffmann-La Roche
Enrollment: 
439
Study Design: 
Phase II, single arm multi-center trial of atezolizumab in patients with locally advanced or metastatic urothelial bladder cancer. Two cohorts were planned: Cohort 1 consisted of 119 treatment naïve patients who were cisplatin ineligible and Cohort 2 consisted of patients who had progressed during or following platinum therapy (see below). The results of cohort 1 were presented at the ASCO meeting for the first time (Balar AV et al). The primary endpoint was objective response rate (ORR) and the secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and the incidence of adverse events.
Rationale: 
PD-L1 checkpoint blockade has recently received FDA approval for metastatic urothelial cancer refractory to standard chemotherapy and the results of Cohort 1 are exciting because this is the use of such therapy as upfront therapy for locally advanced or metastatic urothelial bladder cancer in patients who are ineligible for cisplatin-based chemotherapy.
Comments: 
This is the first study to present atezolizumab as upfront therapy for urothelial cancer. The results are encouraging for the use of checkpoint blockade inhibitors as first line therapy, especially in patients unfit for cisplatin.
Results: 
Most patients were ineligible due to renal impairment. Median follow-up for patients was 14.4 months with ORR of 24% , and responses we seen in all PDL-1 IC subgroups. Responders included patients with poor baseline prognostic factors. Median overall survival was 14.8 months. Severe adverse events were noted in 10–15% of patients including hypothyroidism, liver function abnormalities, rash, and diarrhea, with a low rate of Garde 3-4 side effects.

Study of Bacillus Calmette-Guerin (BCG) Combined With PANVAC Versus BCG Alone in Adults With High Grade Non-Muscle Invasive Bladder Cancer Who Failed At Least 1 Course of BCG

Status: 
Recruiting
Sponsor: 
National Cancer Institute
Participating centers: 
Bethesda and New Brunswick
Accrual: 
54
Study Design: 
Phase 2, randomized trial comparing BCG alone to BCG and PANVAC in high-grade BCG-refractory NMIBC patients. The primary endpoint is 12 month DFS rate. The secondary endpoints are time to recurrence, progression-free survival, and immunologic correlates.
Rationale: 
PANVAC is a vaccine with transgenes for CEA and MUC-1. These tumor antigens are overexpressed on the surface of high-grade urothelial tumors. Also PANVAC contains three co-stimulatory molecules that can augment a T-cell immune response. In theory, the vaccine should augment a T-cell response against cells expressing CEA and MUC-1. Therefore, it is postulated that it will augment the response to BCG when combined with BCG.
Comments: 
An immune response can be triggered either by inhibiting blockade or augmenting T-cell stimulation. PANVAC attempts the latter with three co-stimulatory molecules. By using a systemic vaccine with a local immunotherapeutic agent, this trial attempts to establish greater efficacy than BCG alone.

Phase 1/2 Study of ABI-009 in Non-muscle Invasive Bladder Cancer

Status: 
Recruiting
Sponsor: 
Aadi, LLC
Participating centers: 
New York and Nashville
Accrual: 
estimated 40
Study Design: 
A Phase 1/2, Single Arm Open-Label Study to Determine the Efficacy and the Safety of Albumin-bound rapamycin nanoparticles (ABI-009) in recurrent or BCG-refractory NMIBC patients.
Rationale: 
Rapamycin is an MTOR inhibitor that has demonstrated activity against bladder cancer in preclinical models. Intravesical administration, however, is not practical for most targeted therapies. Nanoparticles may allow for increased delivery of therapeutic agents across the urothelium and has been demonstrated to be active with agents such as paclitaxel. Therefore, now rapamycin is being evaluated in this trial.
Comments: 
Nanotechnology allows delivery of a variety of therapeutics intravesically and has been successfully done with paclitaxel. Therefore, this trial has a lot of potential.

Intravesical Administration of rAd-IFN/Syn3 in Patients With BCG-Refractory or Relapsed Bladder Cancer

Status: 
Completed
Sponsor: 
FKD Therapies Oy
Enrollment: 
40
Study Design: 
Phase II, randomized trial comparing two different doses of rAd-IFN (Instiladrin) in high grade BCG-refractory or BCG-relapsing NMIBC patients. The primary endpoint is RFS at 12 months following four instillations. The secondary endpoint is toxicity and adverse event evaluation. This trial has been completed but results are pending.
Rationale: 
Interferon (IFN) is postulated to be important in BCG-responsive tumors but intravesical IFN ineffective due to short exposure to urothelium. Intravesical IFN production is facilitated by co-administration of recombinant adenovirus (rAd)-mediated IFN-α2b protein, with the excipient Syn3 which improves viral mediated transduction of the urothelium. In a phase I trial of 17 patients, rAd-IFN was well tolerated and 43% (6/13) of patients with detectable IFN-α in the urine achieved complete remission at 3 months that lasted on average for 31 months.
Comments: 
IFN is a logical next step in immunotherapy and adenoviral mediation transduction may improve significantly upon intravesical administration. The impressive complete remission rates in the phase I and II trials are very encouraging. Also it will be interesting to see the duration of IFN detection in the urine post-treatment to establish adequate dosing of Instiladrin. A phase III single-arm registration trial is planned with activation expected in 2016.
Results: 
Preliminary results were presented at the 2015 AUA Annual Meeting. Of 34 evaluable patients at the time of the abstract, 10 patients (29%) had achieved a complete remission at 12 months. Tolerability in these patients was excellent with some minor urinary urgency post-instillation that was managed with oral anticholinergics.

Genetic Susceptibility to Tumor Recurrence and Progression in Patients With Non-Muscle Invasive Bladder Cancer

Status: 
Completed
Sponsor: 
Memorial Sloan Kettering Cancer Center
Participating centers: 
New York, NY
Accrual: 
116
Study Design: 
Observational cohort study of patients with non-muscle invasive bladder cancer that includes genetic assessment of tumors and behavioral questionnaires to establish whether they can enhance the ability to predict tumor recurrence and progression over tumor grade and stage.
Rationale: 
Tumor and grade are not adequate predictors of recurrence and progression in NMIBC and so by identifying behavioral risk factors from questionnaires and genetic susceptibility genes in DNA repair, cell cycle, and detoxifying pathways; perhaps, better prediction of NMIBC outcomes can occur.
Comments: 
Samples will be obtained from blood, urine, and tumor tissue. The study hopes to predict the 40% of patients with NMIBC that may never recur or progress with tumor. The study has accrued 116 patients and analysis is pending. One concern is that often very little tumor tissue is present in NMIBC specimens and instrumented urine may not contain enough urothelial cancer cells for analysis.

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