Emerging Therapies in Clinical Trials for Bladder Cancer

Evolving ParadigmsBladder Cancer
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There are several agents currently in clinical trials for the treatment of bladder cancer.

This article is part V of a series. View parts I,II,III, and IV:Evolving Paradigms in Bladder Cancer> >

There are several agents currently in clinical trials for the treatment of bladder cancer. These agents fall under one of 2 therapeutic approaches: targeted therapy or immunotherapy. Targeted therapies are engineered to detect and eliminate cancer cells while leaving healthy cells unaffected. These therapies usually target molecular pathways, such as Ras and mTOR, which have been deterred specifically in cancer cells. Immunotherapy, which is sometimes referred to as biologic therapy, is used to treat cancers by boosting the patient’s immune responses or by delivering synthetic immune system components to the patient. There are several different types of immunotherapies, including antibodies, vaccines, fusion proteins, bacteria, and small molecule inhibitors (See Table 3).

Table 3. Therapeutic Agents Currently in Clinical Trials for Bladder Cancer

Targeted therapies

Tyrosine kinase inhibitors

Sunitinib is a tyrosine kinase inhibitor that blocks the vascular epidermal growth factor receptor (VEGFR), which plays an important role in angiogenesis and tumor growth. A recent report found that sunitinib treatment in patients with metastatic bladder cancer results in a clinical response after recurrence.100Investigators at the University of Michigan are currently studying the effect of sunitinib treatment following BCG delivery in patients with high-risk nonmuscle-invasive bladder cancer (Sutent trial). While about half of patients with nonmuscle-invasive disease experience a complete response to BCG therapy alone at 3 months, up to one-third of these patients develop recurrent or progressive disease. The Sutent trial will evaluate complete response at 3 months and 6 months, as well as recurrence at 3 years, following combination treatment with BCG and sunitinib.101

Cabozantinib is another receptor tyrosine kinase inhibitor that targets VEGFR and slows angiogenesis. Previous studies have demonstrated its use in the treatment of medullary thyroid cancer, prostate cancer, and ovarian cancer. A phase II study being conducted at the National Cancer Institute (NCI) is investigating its use in advanced and/or metastatic urothelial carcinomas. Overall response rate is the primary outcome of the study.102

Pazopanib is a tyrosine kinase inhibitor that blocks VEGF and is currently being studied in kidney cancer. Combination treatment with pazopanib and paclitaxel was shown to be favorable in a phase I trial. Therefore, an ongoing phase II trial is being conducted at Stanford University to evaluate the effect of combination therapy with pazopanib and weekly paclitaxel in refractory bladder cancer. Patients with first recurrence following chemotherapy and with TCC of the urothelium are eligible for the study. Investigators will assess tumor response rate (complete or partial) using the response evaluation criteria in solid tumors (RECIST) as the main outcome.74

Alisertib is a selective, small molecule inhibitor of aurora kinase A, a protein involved in mitosis and cell proliferation. Overexpression of aurora kinase A has recently been reported in bladder cancer, and dysregulation of spindle checkpoints is common in urothelial carcinoma. The Fondazione IRCCS Istituto Nazionale dei Tumori, Milano is conducting a randomized, phase II trial to study the effects of alisertib plus or minus paclitaxel versus placebo plus paclitaxel on the 2-month response rate and progression-free survival of patients with relapsed or refractory TCC of the bladder and urothelial tract.103

Erlotinib is a reversible tyrosine kinase inhibitor that acts upon epidermal growth factor receptor (EGFR), which is commonly mutated and overexpressed in several types of cancer. EGFR activates the PI3K-AKT-mTOR and Ras-MAPK pathways, which regulate cell growth. Erlotinib is most well-known for its use in the treatment of non-small cell lung cancer and pancreatic cancer. A multicenter, randomized, phase II trial will begin recruiting in October 2014 to investigate the effect of pretreatment with erlotinib versus placebo before surgery (TURBT) on tumor cell growth in patients with bladder cancer. Patients with stages T1-T3 bladder cancer as well as patients with recurrent bladder cancer will be eligible for the study. The main outcome will be phosphorylation of EGFR in the bladder tissue adjacent (normal appearing) to the tumor.104

Afatinib is a second-generation tyrosine kinase inhibitor that irreversibly inhibits human epidermal growth factor receptor 2 (HER2) and EGFR, both of which play crucial roles in cancer cell growth and survival. Similar to EGFR, HER2 is a protein that is commonly overexpressed in cancer and is associated with more aggressive disease. The University of Chicago is conducting a trial to study the effect of afatinib treatment on progression-free survival in patients with refractory urothelial cancer. Patients enrolled in this study have cancers that are unable to be removed surgically and that have progressed following treatment with standard first-line chemotherapy. Similar to the erlotinib study, investigators expect that treatment with afatinib may retard tumor cell growth and/or promote cancer cell death.105

Dovitinib is a receptor tyrosine kinase inhibitor that binds strongly toFGFR3, which plays a role in cell proliferation.FGFR3is commonly mutated in bladder cancer, leading to its constitutive activation and resulting in aberrant cell proliferation. A multicenter, phase II trial is assessing the use of oral dovitinib in BCG-refractory urothelial carcinoma patients harboring tumors withFGFR3mutations or overexpression and who are ineligible for or refusing cystectomy. The primary outcome of the study is the proportion of patients with a complete response 6 months following treatment with dovitinib.106

Monoclonal antibodies

Panitumumab is a monoclonal antibody against EGFR. Investigators at the Memorial Sloan Kettering Cancer Center are conducting a phase II trial to determine if the addition of panitumumab to standard chemotherapy (gemcitabine and carboplatin) will shrink tumors before bladder cancer patients undergo radical cystectomy. Patients included in the study have muscle-invasive TCC of the bladder without metastatic disease. The primary outcome of the study is pathologic complete response rate 1 year after surgery.107

Small molecule inhibitors

Everolimus is an mTOR inhibitor that has been utilized in the treatment of several cancers, including breast, pancreatic, and kidney. mTOR is a serine/threonine protein kinase in the PI3K pathway that is involved in cell growth, proliferation, motility, and survival. It also plays a role in protein synthesis and transcription. There are currently 3 clinical trials of everolimus in bladder cancer. The first is a multicenter, randomized, phase II trial investigating everolimus alone or everolimus plus paclitaxel as first-line therapy in cisplatin-ineligible patients with advanced urothelial carcinoma. The primary outcome is response rate (complete response, partial response, or stable disease) at 4 months from initiation of treatment.108The second study is a phase I trial investigating the safety of standard chemotherapy (gemcitabine and cisplatin) plus everolimus at different dose levels in patients with advanced urothelial cancer. The addition of everolimus to cisplatin has previously been shown to enhance the killing of cancer cells, thus suggesting its therapeutic potential in cancer treatment. The primary outcome of this study is dose-limiting toxicity for everolimus in combination treatment with gemcitabine and cisplatin.109The third study is a phase I/II study at Memorial Sloan Kettering Cancer Center investigating different doses of oral everolimus paired with intravesical delivery of gemcitabine in patients with primary or secondary carcinoma in situ of the bladder and who are refractory to BCG. Dose-limiting toxicity and the maximum tolerated dose will be assessed for this combination therapy as part of the phase I portion of the trial. The primary outcome of the phase II portion of the trial is the proportion of patients who experience complete response at 1 year after the initiation of therapy.110

Temsirolimus is an inhibitor of mTOR and is being investigated in a French, multicenter, phase II study in patients with relapsed bladder cancer. The VESTOR study, as it is named, measures the efficacy of temsirolimus in terms of nonprogression rate, which is defined as the sum of partial response, complete response, and stable disease.81

Nanoparticle albumin-bound rapamycin (Nab-rapamycin) is an mTOR inhibitor that is currently being studied for its use in the treatment of nonmuscle-invasive bladder cancer. Patients included in the study have either recurrent nonmuscle-invasive TCC of the bladder or are refractory to BCG treatment. This study is a phase I/II trial. Phase I primary outcomes are safety and tolerability while the phase II outcome is complete response rate.111


Intravesical therapies

BCG therapy is the most commonly used immunotherapy in bladder cancer treatment. BCG is a live, attenuated strain of Mycobacterium bovis and is the only therapy approved by the FDA for carcinoma in situ of the bladder. Cystectomy is often accompanied by BCG intravesical therapy in bladder cancer patients because it has been shown to reduce the risk of recurrence and tumor progression.32Several agents mentioned in this section are supplements of BCG therapy.

Antibody therapies

Ipilimumab is an antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a protein expressed on the surface of activated helper T cells. CTLA-4 transmits an inhibitory signal to the activated T cell, which down regulates the immune response. Ipilimumab has shown promise as a neoadjuvant therapy for patients with clinically localized bladder cancer undergoing radical cystectomy. A multicenter phase II trial is assessing the effect of gemcitabine, cisplatin, and ipilimumab in the treatment of metastatic urothelial carcinoma. The primary outcome measured is 1-year overall survival.111

MPDL3280A is an antibody against programmed death ligand 1 (PD-L1), a ligand for the PD-1 pathway. When the body encounters a foreign antigen, there is a proliferative response of antigen-specific CD8+ T cells in the lymph nodes and spleen. The PD-1 pathway reduces proliferation of these T cells upon binding of PD-L1 to the PD-1 receptor. Neutralizing PD-L1 restores the accumulation of CD8+ T cells that can counteract tumor cells. A multicenter study being sponsored by Roche is testing the effect of MPDL3280A in patients with locally advanced or metastatic bladder cancer in a phase II trial. Two cohorts will be included. The first cohort will include patients who have received no prior treatment and who are ineligible for platinumcontaining therapy. The second cohort will include patients with platinum-resistant disease. Patients will be followed up to 3 years following treatment, and the objective response rate will be evaluated as the primary outcome.69

Nivolumab is an antibody against PD-1 which is currently being studied by Bristol-Myers Squibb in a phase I/II clinical trial in patients with advanced or metastatic triple-negative breast cancer, gastric cancer, pancreatic adenocarcinoma, small cell lung cancer, and bladder cancer. The trial compares treatment with nivolumab alone versus nivolumab plus ipilimumab and evaluates the objective response rate up to 17 months following treatment.64

Fusion proteins

ALT-801 is a recombinant fusion protein of interleukin-2 (IL-2) and soluble T-cell receptor directed against an antigen driven by the tumor suppressor p53. Tumor cells presenting p53/major histocompatibility complexes (MHC) are bound by ALT-801, resulting in the IL-2 moiety of the fusion protein stimulating natural killer (NK) cells and T-cell cytotoxic immune responses against the tumor cells. Two clinical trials are currently being conducted with ALT-801. The first is a phase Ib/II multicenter trial studying the addition of ALT-801 to gemcitabine in patients with nonmuscle-invasive bladder cancer who have failed BCG therapy. Safety and tolerability will be assessed within the first 12 weeks following treatment. Additionally, the proportion of patients with a complete response will be measured as a primary outcome.40Another similar trial will evaluate the addition of ALT-801 to either gemcitabine alone or the combination of gemcitabine and cisplatin in patients with muscle-invasive or metastatic urothelial cancers. Primary outcomes will be the maximum tolerated dose and/ or recommended dose for ALT-801 in both treatment regimens. Safety will be assessed as well as the number of participants with an objective response, including complete response, partial response, or stable disease.39

ALT-803 is a fusion protein complex of superagonist interleukin-15 (IL-15) and a soluble, dimeric IL-15 receptor alpha Fc fusion protein. ALT-803 binds to the IL-2/IL-15 receptor beta-common gamma chain receptor on NK and CD8+ T cells, activating these immune cells and inducing their expansion. A phase Ib/II, multicenter study is determining the effect of combination therapy with BCG and ALT-803 in patients with nonmuscle-invasive bladder cancer who have not received prior BCG therapy. Safety, maximum tolerated dose, and recommended dose are the primary outcomes.41

Viral therapies

CG0070 is an oncolytic adenovirus that encodes granulocyte macrophage-colony stimulating factor (GM-CSF). This virus selectively infects tumor cells and replicates in them, potentially leading to tumor cell lysis. At the same time, the GM-CSF expressed by the virus may stimulate cytotoxic T-cell responses against tumor cells. There are 2 clinical trials currently being conducted with CG0070 in bladder cancer. The first is a doseescalation study designed to evaluate safety, maximum tolerated dose, and recommended dose of intravesical CG0070 for bladder cancer in patients who have failed BCG therapy.112The second study is a phase II/III randomized, controlled study named BOND that is investigating the efficacy of CG0070 in nonmuscle-invasive bladder cancer. Patients included in the study have TCC, bladder cancer, carcinoma in situ, or carcinoma in situ with papillary tumors. The phase II outcome of this study is the proportion of patients achieving complete response 9 months after treatment. The phase III outcome is the proportion of patients with durable complete response 15 months following treatment.113

Vaccine therapies

NY-ESO-1 is a cancer-testis antigen found in normal testis and overexpressed in many tumor types. An NY-ESO-1 peptide vaccine has been developed to stimulate the immune system to mount antitumor responses to cells expressing NY-ESO-1 antigen, resulting in tumor cell lysis. A phase I trial is being conducted to evaluate the safety and dosing schedule for NY-ESO-1 vaccine therapy with or without sirolimus treatment in patients with solid tumors expressing NY-ESO-1, including recurrent and stage 4 bladder cancers. Secondary outcomes will measure NY-ESO-1-specific cellular and humoral immunity.114

HS-410 is an allogenic urothelial bladder cancer cell vaccine that expresses a recombinant, secretory heat shock protein gp96 fused with an Fc domain from an immunoglobulin (Ig). HS- 410 administration results in continuous secretion of gp96-Ig in irradiated tumor cells, which enhances presentation of tumorassociated antigens to cytotoxic T cells and induces an antitumor response. A phase I/II trial is investigating administration of HS-410 in patients with nonmuscle-invasive bladder cancer. The phase I portion will assess safety and tolerability of HS-410 in these patients. The phase II portion of the study will evaluate if disease-free survival is improved 1 year after treatment with BCG combined with HS-410 compared with placebo.60

PANVAC is a viral cancer vaccine that expresses mucin-1 (MUC-1) and TRIad of COstimulatory Molecules (TRICOMTM), proteins overexpressed by many cancers. When cancer cells become infected with PANVAC, MUC-1 and TRICOM are expressed and presented along with other tumor-associated antigens. The immune system associates these proteins with viral proteins and mounts a response to them, potentially killing tumor cells. A randomized, phase II study is investigating whether the addition of PANVAC to BCG therapy has improved disease-free survival over the course of 5 years compared with BCG therapy alone. Patients included in the study have high-grade nonmuscle-invasive bladder cancer and have failed prior BCG therapy.115

MAGE-A3 is a peptide cancer vaccine comprised of a peptide from the human melanoma antigen A3, which is expressed in a variety of cancer types, including bladder cancer. MAGE-A3 acts as an immunostimulant by inducing a cytotoxic T cell response against tumor cells that express MAGE-A3. A randomized, placebo-controlled, phase II trial is evaluating the safety and efficacy of MAGE-A3 plus the vaccine adjuvant AS-15 in patients with MAGE-A3+ muscle-invasive bladder cancer after cystectomy. The primary outcome of the study is disease-free survival 5 years following cystectomy.116

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