Neoplasms

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Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Antineoplastic Agents

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Gemcitabine

Antibodies

Cisplatin

Immunoglobulins

Magrolimab

Antimetabolites

Antineoplastic Agents, Immunological

Magrolimab therapy in combination with standard first line platinum-based chemotherapy (with Cisplatin / Gemcitabine) in advanced urothelial carcinoma.

Magrolimab in combination with cytotoxic chemotherapy in advanced urothelial carcinoma

Standard first line platinum-based chemotherapy in advanced urothelial carcinoma

Bernhard Kiss, Professor

Berna Özdemir, Doctor

Anselm Lafita

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.

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.

Prospective investigator-initiated single-arm, phase 1 clinical trial, risk category C

Magrolimab in Combination With Cytotoxic Chemotherapy in Advanced Urothelial Carcinoma

A Phase 1, Single Arm Investigator-initiated Study to Investigate the Safety of Combining the Antibody Magrolimab With Standard First Line Platinum-based Chemotherapy (With Cisplatin / Gemcitabine) in Advanced Urothelial Carcinoma

Incidence of AEs including any laboratory abnormalities according to CTCAE, version 5.0

All AEs from start of treatment with IMP until 28 days after the last IMP dose or the initiation of subsequent anticancer therapy, whichever is sooner

Incidence of DLTs in participants of the safety run-in phase

Proportion of participants with any AEs of severity grade 3 or higher according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 over 6 months after IMP dose initiation

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

DOS, defined as date of dose initiation to death from any cause.

The proportion of patients who achieve a complete response or partial response (ORR), as measured by response evaluation criteria in solid tumors (RECIST version 1.1, as determined by investigator assessment

Spots Global Cancer Trial Database for antibody drug therapy