Pembrolizumab in MarginalzoneLymphoma A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY

For marginal zone lymphoma (MZL) Rituximab in combination with conventional chemotherapy is widely used for those patients who fail local therapy or do not qualify for such. Depending on the MZL subtype Rituximab/chemotherapy is able to induce in part long remissions, but does not prevent relapse later on. In addition, chemotherapy associated toxicity is often problematic in MZL patients, who are mostly of advanced age. Thus, chemotherapy-free approaches are highly attractive for this patient group. Rituximab single agent is a widely used chemotherapy-free approach in MZL, but was significantly inferior compared to Rituximab/chlorambucil in a large randomized prospective clinical trial in treatment naïve MZL with a CR rate of 55.8% vs. 78.8%, respectively (P \< 0.001). Thus, it is the major aim to develop chemotherapy-free approaches for MZL, which approach or surpass efficacy of rituximab/chemotherapy combinations, but avoid chemotherapy associated toxicities. Checkpoint inhibitors such as Pembrolizumab have revolutionized cancer treatment and have also shown first encouraging results in Non-Hodgkin lymphomas. Based on these observations it is the aim of this study to test the toxicity and efficacy of Pembrolizumab in combination with the anti-CD20 antibody Rituximab in patients with newly diagnosed or relapsed MZL in need of treatment, who are not eligible or failed local therapy, following the assumption that this novel chemotherapy-free combination is significantly more efficient than Rituximab single agent therapy and at least as efficient as rituximab/chemotherapy, but avoids chemotherapy-related toxicity. The objective of the trial is to test the efficacy and toxicity of treatment with Pembrolizumab and Rituximab in patients with MZL in need of treatment, who have failed or are not eligible for local therapy or relapsed. For efficacy the rate of complete remissions (according to the GELA criteria for gastric MALT or to the Cheson 2007 criteria for nodal and splenic MZL) after end of treatment (18 cycles) will be primarily analyzed. For toxicity assessment treatment associated adverse events, quality of life and cumulative incidence of secondary malignancies will be documented. This study is a European multicenter, single-arm, open-label, phase II trial of 18 cycles of Pembrolizumab and Rituximab in patients aged ≥ 18 years with previously untreated or relapsed MZL in need of treatment. Primary endpoint is the complete response (CR rate (CRR) determined after end of treatment (18 cycles). The study flow will be as follows: * Previously untreated or relapsed patients will be screened for eligibility for the trial. If the patient is eligible for the study, the patient will be registered before the first cycle of treatment. * Patients who progress at any time point during treatment are considered as treatment failure. They will be followed up for overall survival until end of follow up period or death. * Patients, who achieve at least a SD after treatment will be followed up for response until progression/relapse and for overall survival until death. It is expected that a total of 56 patients at approximately 15 investigator sites in Germany and 3 centers in Austria will be registered. Every patient will receive treatment over a time period of 18 cycles (each cycle lasts 3 weeks). Subsequently, patients will be monitored every 3 months for 2 additional years, subsequently every 6 months for three additional years. The follow-up phase will be shorter than 5 years if End of Study is reached before this time period.