02.02.2014

Clinical trials for bladder cancer in canada

Our team of urologists, medical oncologists and radiation oncologists work together to provide the most comprehensive care for patients with bladder cancer. Treatment may include surgery or a combination of surgery, chemotherapy and radiation therapy. Bladder cancer is the sixth-most common cancer in the United States with most people diagnosed at 70 years old or older. Bladder cancer occurs about four times more often in men than in women and is almost twice as high in Caucasian men as in African-American men.
Smoking is the greatest risk factor for bladder cancer and is estimated to cause half of all bladder cancers in both men and women. Donations to UW Health are managed by the University of Wisconsin Foundation, a publicly supported charitable organization under 501(c)(3) of the Internal Revenue Code.
As expected, the major theme this year was (again) Immuno-oncology with a focus on PD-1 antibodies. While the PD-1 arena is dominated by large pharmas, led by BMS (BMY), Merck (MRK) and Roche, investors who would like to get exposure to the personalized medicine paradigm have Foundation Medicine (FMI), which is emerging as the gatekeeper of genomic profiling. As expected, PD-1 antibodies were the focus of attention, with a horse race between BMS, Merck and Roche.
Durable responses – As monotherapy, PD-1 antibodies lead to deep and durable responses in melanoma (30%), renal cancer (20%) and NSCLC (20-30%).
Updated survival data – The survival figures in melanoma and renal cancer were impressive and likely represent clinical benefit for most patients (including non-responders). As one would expect from effective immunotherapy, trials with longer term follow up demonstrate flattening of the survival curve.
New indications – Activity seen in new tumors included response rates of 20% in PD-L1+ head and neck cancer, 43% in PD-L1+ bladder cancer and 17% in ovarian cancer. PD-L1 expression – PD-L1 expression appears to correlate with a higher response rate and is used for patient selection in some of the ongoing pivotal trials.
Combination data – Identifying the right combination regimens for each indication is complex and is perceived as the next stage in the immuno-oncology revolution.
Yervoy as adjuvant therapy– Yervoy (Anti-CTLA4) had impressive efficacy in the adjuvant setting in melanoma (25% reduction in risk of recurrence free survival).
Targets beyond PD-1 – A major ongoing effort is to identify additional immune checkpoint or co-stimulatory molecules that can work in synergy with PD-1.
Vaccines are becoming popular again – As PD-1 antibodies modulate the suppressive tumor microenvironment, they are viewed by many as enablers of cancer vaccines.
Today each of these drugs comes with a dedicated companion diagnostic kit that has to be purchased and analyzed separately in order to decide whether a patient is eligible for the drug. This year’s meeting saw the emergence of 4 new niche indications in clinical trials for 4 different classes of drugs.
MET amplification – Amgen (AMGN) presented phase I results for AMG337, a selective MET inhibitor. TrkA fusions – Ignyta (RXDX) presented phase I data for RXDX-101, a multi-kinase inhibitor of ALK, ROS and Trk. NGS offers higher sensitivity – In addition to the logistic advantages, NGS is potentially superior to available diagnostic methods (FISH, PCR). Founation Medicine, through its commercial products and collaborations with drug development companies is the undisputed leader of tumor genomic profiling. Broad reimbursement remains an important gating factor and is still several years away, as HMOs are reluctant to provide automatic coverage without prospective clinical data, FDA approval or incorporation in the medical community’s guidelines. Importantly, several new drugs are expected to utilize Foundation Medicine’s technology.
NGS has its limitations and will have to be used in combination with other methods in order to get a full profile of the tumor (for example, PD-L1 status is assessed with standard IHC) but it appears to be the only viable route to cover many of the known actionable mutations. This entry was posted in kinase inhibitors, Monocloncal antibodies, Uncategorized and tagged ABBV, AGIO, ARRY, AZN, BMY, CLVS, FMI, JNJ, MRK, RXDX by Ohad Hammer. I know MRTX is also involved in targeting Trk (among other targets) with their second drug. Re MET and Axl, in preclinical experiments both were implicated to EGFR resistance but I am not aware of any substantial proof in the clinic. Tarceva is an EGFR inhibitor, which is why it is used in combo with Met inhibitor for EGFR resistance based on preclinical data of upregulation of the MET kinase found in over 50% of EGFR resistant tumors, which has NOT panned out after years in clinic yet. Christian – From what I see the updates are incremental and do not provide any meaningfully new data. Re Merck Serono’s PD-L1 mAb, data for this program are very limited, the ASCO poster disclosed 1 PR of 28 patients. Ohad, I do agree Met inhibitors quite possibly find success in much more selective patient population. Ohad, on AMBI, isn’t the additional data showing that bridge to transplant isn’t really resulting in a true cure like was hoped?
Ohad, would it be possible to ask why Kite is proceeding on targeting the EGFRvIII location with a CART for GBM patients?
Declan (ARRY) – My take from ASCO is that MEK inhibtors are going to be a much bigger class than originally thought (intersting data in BRAF+ CRC, RAS+ ovarian on top of melanoma and lung).
New research from the Medical College of Georgia at Georgia Regents University (GA, USA) concludes that older, single white males with advanced bladder cancer are at highest risk of suicide when compared with other comparable individuals with genitourinary cancers. The study, recently published in the journal Cancer, is one of the first assessments of the risk of suicide in this demographic.
The rigorous treatment and recovery schedule for aggressive bladder cancer is well documented, with close follow-up for signs of metastasis. Further analysis demonstrated that older people with bladder, prostate or testicular cancer had a general increase in suicide risk. In an accompanying editorial, it was also noted that increased age is associated with suicide in general, as well as in cancer patients.
Statistics from the American Cancer Society show the average age of bladder cancer diagnosis is 73 years and approximately 90% of bladder cancer patients are over 55 years. According to Centers for Disease Control and Prevention figures, suicide is the tenth most common cause of death, while cancer is the second most common. In further investigations the researchers want to reanalyze these patient groups, investigating any signs of prior psychiatric issues and the effect of any treatments, such as antidepressants, which may influence their conclusions. Source: Medical College of Georgia at Georgia Regents University news release via EurekAlert!
Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) has been used by urologists worldwide and was approved in 1990 by the US Food and Drug Administration. This content is created by the Healthline editorial team and is funded by a third party sponsor.
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As the fastest growing consumer health information site a€” with 65 million monthly visitors a€” Healthlinea€™s mission is to be your most trusted ally in your pursuit of health and well-being. Prof John Betteridge reviews the impact of various diabetic drugs on glycemic control, vascular prevention and Beta cell function.


Prof John Betteridge, London, discusses the evolution of diabetes therapy, the epidemic rise in diabetes, current and emerging diabetes therapies. Treatment with pioglitazone to improve insulin sensitivity, reduced stroke and MI in patients with insulin resistance but without diabetes and who have experienced ischaemic stroke or TIA. In patients with type 2 diabetes and angiographic coronary artery disease, treatment with pioglitazone resulted in larger LDL particle size and decreasing concentrations, associated with less plaque progression. A 10-year post-marketing study in patients with type 2 diabetes demonstrated no statistically significant increased risk of bladder cancer to patients exposed to pioglitazone.
We also offer several innovative options for early stage and advanced bladder cancer, including continent urinary diversion, which provides patients with an excellent quality of life. Another theme that is gaining momentum is segmentation of tumor types to small niches based on high resolution genomic profiling.
In melanoma, median overall survival was 17 (heavily pre-treated) and ~24 months (limited prior therapy, estimated) for nivolumab and pembrolizumab (MK-3475). This implies that for some patients, PD-1 antibodies may offer long term remission or even a cure. Some of the trials had limited follow up so response rates may improve at the next analysis. Combination data for nivolumab+Yervoy continue to look promising in melanoma and renal cancer but clinical profile in NSCLC is uninspiring with limited efficacy and significant toxicity. This is seen as a validation for immune checkpoint blockers and has already prompted adjuvant trials with PD-1 antibodies.
The next hot target is OX40, pursued by Roche (disclosed at its analyst event) and AstraZeneca. PD-1 antibodies are expected to rime the immune system in general while vaccines will guide the immune system to the right antigens. NGS, which enables genomic profiling of many biomarkers in parallel, will likely become the mainstay of cancer diagnostics given the increasing number of drugs intended for genetically defined tumors.
This means that in order to find out if a patient is eligible for a specific drug, cancer centers will have to run many tests, which will become unfeasible from a logistic as well as economic perspective. Of a total of 45 patients 5 had FGFR fusions or translocations, of whom three achieved a response (ongoing) and one experienced disease stabilization (8 months). The trial enrolled patients with relevant genomic alterations and results include responses across all 3 subtypes. At ASCO, Foundation Medicine presented several data sets, the most striking one was from a study which suggests that Foundation’s product is more sensitive in identifying ALK+ tumors than the approved method (FISH). The company’s products, FoundationOne and FoundationOne Heme are commercially available and are already generating significant sales with a limited sales force. Reimbursement and market adoption will rely on clinical data with approved and investigational drugs, demonstrating FMI’s ability to guide treatment decisions. The most visible example is Agios’ (AGIO) IDH2 inhibitor  (AG-221) which generated phenomenal results in AML. Similarly to the case with biotech stocks, the rationale for holding the stock lies in the huge market potential down the road. The NGS market is expected to grow exponentially over the coming years, which makes Foundation Medicine an obvious acquisition target given its first mover advantage and market experience. Changing the dosing regimen should allow better target coverage and we know the effective ALK inhibitors are all given daily. The subset of EGFR progressors who are not T790M represents an attractive opportunity, no doubt, but burden of proof is on MRTX.
Is it too early to tell which CAR-T companies will survive, or do you have a favorite already? Axl can be an interesting target on a standalone basis if Axl rearrangements are validated as oncogenic drivers.
The next important readouts will be for the maintenance study (only 13 patients but company hints results are robust) and combination studies including earlier stage patients.
I read up on the preclinical results and there seems to be an effect within 10 or so days, but a couple of weeks after that, the untreated and treated mice both had the same amount of tumor mass.
I agree that the apparent benefit is limited and could reach increased OS of several months. So much time and money were put into cancer vaccines in the past decades and if investigators can revive all those terminated programs with PD-1 then the benefit would be huge. Don’t know about their CAR programs, I would be surprised if they enter the clinic before mid 2015. Also, I am not too excited about their HER2 antibody for gastric cancer but we’ll see data soon. Their platform is back to square 1 in terms of validation and their drugs have an unfavorable PK profile. The review identified the previously described patients’ suicide as a public health dilemma, which warrants physician vigilance.
Variables such as age, sex, race, as well as disease and treatment aggressiveness were also examined. When analyzing the black population specifically, individuals with bladder cancer were at increased risk of suicide, however black individuals with bladder, prostate and kidney cancer had lower suicide rates than white people within the same parameters. There are approximately 74,000 new cases of bladder cancer recorded in the USA each year, with males and smokers at increased risk.
Suicide rates in the general population are experiencing an upward trend, with the estimated current rate at 13 deaths per 100,000 individuals annually. In order to post comments, please make sure JavaScript and Cookies are enabled, and reload the page. In order to register, please make sure JavaScript and Cookies are enabled, and reload the page. These advantages are seen mainly when appropriate maintenance therapy is used for 1–3 years, in the context of appropriate patient selection, tumor management, and symptom support for potential side effects.
After 23 yr, it is fair to say that BCG remains the only truly effective intravesical therapy for non–muscle-invasive bladder cancer (NMIBC), with proven effects reducing recurrence and prolonging survival.
BCG has been proven to decrease both progression and recurrence based on evidence from high-quality meta-analyses and randomized controlled trials (RCTs) [1], [2], and [3]. What the authors fail to recognize is that there was a clinically relevant difference in outcomes between the groups. Current evidence clearly shows that intravesical BCG should be administered according to the protocol described in SWOG trial 8507 [5].
The use of adjuvant intravesical therapy after transurethral resection of bladder lesions is recommended based on the likelihood of recurrence and progression. As highlighted by our discussions, BCG therapy administered diligently and with adequate maintenance therapy in patients with intermediate- and high-risk NMIBC positively affects patient outcomes by decreasing recurrence and progression and improving disease-specific survival, as shown by multiple high-quality, well-performed, multi-institutional clinical trials. Kamat is on the advisory board of Endo Pharmaceuticals, of Bioniche, and of Sanofi-Pasteur. The content is objective, medically accurate, and adheres to Healthline's editorial standards and policies.
Both of which will support, guide, and inspire you toward the best possible health outcomes for you and your family.


This approach can be used to identify a drug’s target population already in phase I, as exemplified by multiple presentations I will discuss below. Updated response data at ASCO were lower than expected but it appears that response rate does not fully capture the overall benefit of PD-1 drugs. PD-1 antibodies are combinable with chemotherapy and targeted therapies with some encouraging signs but safety issues emerge.
Foundation’s tests solve this problem in an elegant way by providing mutational status for many relevant genes in a single test.
While activity in patients with ALK and ROS-mutated tumors may not be as strong as with other drugs, there was one impressive response in a colon cancer patient with a TrkA fusion mutation. The abstract reports 9 patients whose tumors were classified as ALK- by standard assays but as ALK+ using NGS. In order to select patients for its clinical trial, Agios uses Foundation One, which will become AG-221’s companion diagnostic test.
Beyond PD-1, it appears they have multiple I-O programs in preclinical development so I expect significant news flow on that front. From a scientific and execution standpoint, one of the most impressive stories out there (yes, they’re the only ones with an XPO1 inhibitor I am aware of) but data ar still early and valuation is high imo. It was discovered that patients with bladder cancer, regardless of surgery or aggressiveness, were at higher risk of suicide than any other genitourinary cancer patients. It was demonstrated that prostate cancer patients had an increased suicide risk over time, with the highest rate 15 years or longer after initial diagnosis. Specifically, using a meta-analysis of 24 RCTs evaluating BCG in >4000 patients with NMIBC, Sylvester et al. Induction consists of six weekly intravesical instillations of BCG, followed by maintenance consisting of three weekly treatments at 3 mo and 6 mo and then every 6 mo, for a total of 36 mo. The beneficial effect of BCG is greatest in those with both intermediate- and high-risk disease [1], as only those with low-grade and low-volume Ta tumors (low risk) have a <5% probability of progression. In the aforementioned EORTC 30962 study comparing full-dose and one-third dose intravesical BCG immunotherapy given with a 1-yr or 3-yr maintenance course, there were no significant differences in side effects based on dose or duration of maintenance schedule given [10]. It is critical, however, to adhere to the principles outlined earlier because mismanaging intravesical therapy can lead to disastrous consequences for our patients. The content is not directed, edited, approved, or otherwise influenced by the advertisers represented on this page, with exception of the potential recommendation of the broad topic area. In most cases, these drugs are ineffective in the general population but highly effective in rare subsets of cancer patients.
In all cases, the survival appears better than historical controls, but the single arm trial design warrants caution in interpreting the data.
As this was the only TrkA+ patient in the trial and given the limited follow up, it is still hard to declare TrkA as a novel target. The phenomenal efficacy of the drug in IDH2+ patients, should make FMI’s test a standard diagnostic test for every newly diagnosed AML patient.
Note that Yervoy+GP100 was not superior to Yervoy mono in one of Yervoy’s pivotal trials. These misconceptions regarding BCG often stand in the way of its delivery and optimal care of our patients. For example, continued BCG in the setting of high-risk recurrence can lead to progression of tumors, including metastatic disease, and can miss the opportunity of cure for the patient.
Nevertheless, the quick and significant response is reminiscent of other genetic niches such as ALK and RET. Assuming a US incidence of 18,000 and a price of $3000, the AML market represents a $54M opportunity every year in the US alone.
This benefit was seen in both papillary and carcinoma in situ (CIS) lesions but, importantly, was noted only in trials that utilized maintenance therapy in addition to induction therapy.
Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. Maintenance therapy with bacillus Calmette-Guerin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guerin therapy of superficial bladder cancer. Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guerin (BCG): results of an international individual patient data survey (IPDS). Some experts claim that maintenance does not work; they are likely referring to past studies showing differences in patient outcomes with induction BCG alone but compared with suboptimal maintenance schedules (Fig.
Contrary to previous reports with dismal rates of discontinuation of intravesical treatment ranging from 20% to 80% due to side effects, more contemporary evidence suggests that BCG is, in fact, mostly well tolerated.
However, once the treating community adopts appropriate standards for BCG regimen, we can focus on improvements in patient selection, response assessment, and ways to predict which patients will or will not benefit from intravesical immunotherapy. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials.
1), such as 6-wk induction therapy followed by monthly maintenance [7] or one instillation every 3 mo [8].
This study demonstrated BCG's superiority compared with intravesical epiribucin and provided compelling evidence with long-term end points to recommend the use of BCG for intermediate-risk disease [1]. Patient education, screening and treatment of preexisting bacterial cystitis, delay of intravesical instillation in the face of severe chemical cystitis, and use of a short-course fluoroquinolone antibiotic can help increase tolerability of BCG immunotherapy. Furthermore, when this occurs, we can focus our energy toward elucidating the underlying mechanisms of both host and tumor responses to BCG treatment and identify appropriate mechanism-based combination therapies for nonresponders. These are crucial next steps, but they can be adequately studied only when the primary therapy is standardized.
Single course versus maintenance bacillus Calmette-Guerin therapy for superficial bladder tumors: a prospective, randomized trial. The risk of recurrence and progression is lifelong in these patients, and induction therapy alone is not enough to produce prolonged immune stimulation necessary for optimal patient outcomes. Thus, at this time, it remains imperative that we shed our prejudices and misconceptions, dispel the myths surrounding BCG therapy, and provide aggressive, appropriate adjuvant intravesical treatment to improve outcomes in patients with intermediate- and high-risk NMIBC [11]. Furthermore, being an immune-modulatory therapy, the dose and duration of treatment are of paramount importance and likely are related to various factors such as patient age and tumor characteristics. They found that full dose for 3 yr was most effective in reducing recurrences of high-risk disease, whereas for intermediate-risk disease, full dose for 1 yr was most effective.



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