Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma.

MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 µg/kg/dose with 6,000 µg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 µg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (n = 12), overall response rate was 41.7% (complete response, n = 2; partial response, n = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events. Significance: This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising.

Clinico-laboratory pertinences and management of relapsed and refractory.

PURPOSE: The purpose of this study was to assess the biological significance of lactate dehydrogenase (LDH), T315I mutation and treatment options in newly diagnosed and relapsed patients with chronic myeloid leukemia (CML). METHODS: Our clinical-analytical and descriptive study enrolled 27 patients with different phases of CML, who were followed up and treated at the Institute of Oncology between 1995-2020. Venous blood samples were taken for LDH measurement, molecular screening and detection of T315I mutation of the ABL gene in order to investigate the biological significance of the increased LDH values and T315I mutation. CML patients underwent chemotherapy with alkylating agents, antimetabolites and tyrosine kinase inhibitors (TKIs). RESULTS: The patient age ranged from 20 to 67 years (mean 51.3±2,14). The diagnosis of CML was established in the late chronic phase in 25 (92.6%) patients. The quantitative real-time PCR revealed p210 transcript of the BCR-ABL chimeric gene in all cases, with the range of 23.17-100% and median value of 74.73±3.21%. LDH at diagnosis ranged between 169-1609.4 U/L and was increased in 14 (63.6%) patients, especially in those with leukocytosis over 100x109/l. The complete cytogenetic and complete or major molecular responses were recorded under treatment with different generations of TKIs in 16 (59.3%) cases, including 3 cases with T315I mutation. Relapses occurred in 10 (71.4%) patients with initially increased LDH values and in 5 of 6 patients with T315I mutation. One (3.7%) patient with T315I mutation evolved into the acute phase disease, and achieved the complete hematological response after treatment with ponatinib, a 3rd generation TKI. The survival of patients from the disease onset till the last monitoring visit ranged between 21 and 234.8 months (median 93.97±4.52). CONCLUSIONS: The increased LDH values may indicate the activity at diagnosis and relapse of CML. In our study T315I mutation of the ABL gene and the increased values of LDH were associated with a higher rate of relapses and resistance to imatinib. Notwithstanding the treatment line and in relapses TKIs improve considerably the survival and ECOG-WHO score of CML patients.

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.