MesoPher/Mitazalimab-combination Therapy in Metastatic Pancreatic Disease (REACtiVe-2 Trial)

Rationale: Pancreatic cancer is expected to be the second leading cause of cancer-related death in 2020. Pancreatic cancer is known as an immunological cold tumor. It is thought that the characteristic desmoplastic stroma of established pancreatic adenocarcinomas acts as a physical as well as an immunosuppressive barrier leading to exclusion of T cells. The use of CD40 agonists (such as mitazalimab, also known as JNJ-64457107 and ADC-1013) may convert pancreatic adenocarcinomas into immunological hot tumors by T-cell-dependent and T-cell-independent mechanisms. Targeting the desmoplastic stroma, thereby making the tumor more permeable for T-cell infiltration, is seen as one of the assisting mechanisms. Furthermore, the immunological coldness of pancreatic cancers infers that tumor-reactive T-cell responses are absent or weak at best. Dendritic cell therapy introduces tumor-specific T cells and in combination with a CD40 agonist, may lead to synergistic anti-tumor responses which could be beneficial for pancreatic cancer patients. Objective: To investigate safety and tolerability as well as the induced immune response upon MesoPher/mitazalimab combination therapy in metastasized pancreatic cancer after standard-of-care (SOC) treatment with (modified) FOLFIRINOX. Study design: Open-label, single-center, phase I dose finding study using a modified toxicity probability interval (mTPI) design. Study population: Adults with metastatic pancreatic cancer after SOC treatment with (modified) FOLFIRINOX. Intervention: Leukapheresis is performed after which monocytes are used for differentiation to dendritic cells. Autologous dendritic cells pulsed with an allogeneic tumor lysate (MesoPher) will be administered intra-dermally and intravenously 3 times every 2 weeks. Booster vaccinations are given after 3 and 6 months. On the same day after administration of MesoPher a CD40 agonist (mitazalimab) will be administered intravenously. Study parameters/endpoints: The main study endpoint are the dose-limiting toxicities of MesoPher/mitazalimab combination therapy. The secondary endpoints are the induced immune responses on therapy and the radiographical response rate according to RECIST and iRECIST. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients have to undergo additional outpatient clinic visits for this study and additional invasive procedures specifically for this trial, e.g. intravenous catheter placement and tumor metastasis biopsies. Although these are invasive procedures, associated risks are limited. Intravenous access is necessary during every visit, i.e. for leukapheresis, for drawing blood samples and for the administration of study medication. Leukapheresis is a standard procedure and will be performed according to our institutional guidelines. Leukapheresis demonstrates a limited risk for transient thrombocytopenia and leukopenia. Previous clinical studies have shown that injection with tumor lysate-pulsed dendritic cells (MesoPher) was well tolerated without major systemic toxicity, with the exception of low-grade flu-like symptoms (REACtiVE Trial, NL67169.000.18; DENIM/MM04: NCT03610360; MM03 NL44330.000.14 / NCT02395679). Also, intravenous injection of mitazalimab up to 1200 µg/kg was well tolerated with manageable side effects. There are currently no trials investigating this combination therapy. Combining two immunomodulatory drugs increases the risk for toxicity. The objective of this phase I study is to investigate safety and tolerability of administrating MesoPher/mitazalimab combination therapy in metastatic pancreatic cancer patients. Patients may have potential beneficial anti-tumor responses following study medication.