About 10% of the patients with urothelial carcinoma of the bladder present with advanced disease at time of diagnosis. The five-year overall survival is poor (13%) as treatment options are limited to platinum-based chemotherapy and immune checkpoint inhibitors. Therefore, new therapeutic approaches are urgently needed.~Stimulation of the innate immune response to cancer cells using macrophages to attack tumor cells represents a novel approach of cancer immunotherapy. One mechanism used by tumor cells to prevent phagocytosis and thus avoid clearance by the immune system is to up regulate don't eat me signals such as CD47. Blockade of CD47 represents a novel immunotherapy allowing the immune system to eliminate cancer cells. Cytotoxic chemotherapy, in particular Gemcitabine, is known to upregulate calreticulin which is a so called eat me signal. Consequently, a combination of Gemcitabine with an anit-CD47 antibody could potentiate the tumor-cell killing effects.~Magrolimab is a first-in-class fully humanized monoclonal antibody blocking CD47 and currently investigated as an immunotherapy in solid as well as hematologic malignancies in several phase 1 - 3 clinical trials. Furthermore, Magrolimab as a novel myeloid specific immune checkpoint inhibitor could be the urgently needed new therapeutic weapon for bladder cancer treatment if it proves to add a significant therapeutic benefit to conventional chemotherapy in advanced muscle invasive bladder cancer. The expected benefit of combining chemotherapy with Magrolimab might be manifold:~It could result in durable systemic anti-cancer responses and subsequently increase disease free and overall survival~It could increase the response rate and prolong survival in the metastatic setting~In case of positive results of this trial, the investigators could expand this approach to the peri-operative setting:~In the neoadjuvant setting, it could increase the rate of pathologic complete remission (pCR, ypT0) and subsequently reduce the risk of local recurrence and bladder cancer related death~In the adjuvant setting, it could induce antitumor immune response in micro metastases and subsequently reduce risk of local recurrence and improve cancer specific survival.~The primary endpoint of the trial is incidence of adverse events (AEs) and laboratory abnormalities according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 Secondary endpoints are~PFS from date of dose initiation as determined by investigator assessment per RECIST, Version 1.1~DOR, defined as time from first documentation of complete response or partial response to the earliest date of documented disease progression, per RECIST, Version 1.1, or death from any cause, whichever occurs first, as determined by investigator assessment~OS, defined as date of dose initiation to death from any cause.
In their Magrolimab research project, the investigators want to find out whether the new drug Magrolimab in combination with conventional chemotherapy is well tolerated and whether survival or progression-free survival improves.