BACKGROUND: Multiple myeloma is a rare form of cancer that affects the proper function of plasma cells in the immune system. Patients experience symptoms ranging from bone pain to otherwise avoidable infections that can have negative effects on quality of life. Despite advances in multiple myeloma treatment leading to longer patient survival, it is still an incurable form of blood cancer. As a result, it is important for researchers to constantly investigate new avenues of treatment in order to delay disease progression. This study investigated whether the next generation proteasome inhibitor, ixazomib, could safely delay disease progression in patients who failed a combination regimen that included either the proteasome inhibitor bortezomib or carfilzomib. METHODS: This study is a phase 1/2, 3+3 design, intra-patient, multicenter, open-label, and non-randomized clinical trial that recruited patients that were previously on one of ten combination treatments containing the proteasome inhibitors bortezomib or carfilzomib. Patients must have shown progressive disease while on this treatment in order to qualify. They were given the same drugs and doses they were previously taking except that the proteasome inhibitor was replaced with ixazomib. The safety and efficacy measurements were taken periodically to assess patients’ disease burden. To assess safety, adverse events (AEs) and serious adverse events (SAEs) were recorded, codified, and quantified for analysis. In addition, the maximum tolerated dose (MTS) of ixazomib for three regimens for which it was unknown was investigated through the analysis of dose limiting toxicities (DLTs). Clinical benefit rate (CBR) and overall response rate (ORR) using response data were also determined. Lastly, Kaplan-Meir statistical analysis was used to calculate the secondary efficacy endpoints such as progression free survival (PFS) using data collected throughout the trial. RESULTS: Safety: 24.4% of patients experienced at least one ≥ Grade 3 serious adverse event, 33.3% experienced at least one ≥ Grade 3 adverse event, and two experienced dose limiting toxicities. Efficacy: ORR was 13.2% and the CRR was 18.4%. Median PFS was 2.1 months, duration of response (DOR) was 2.0 months, and overall survival (OS) was 7.9 months. However, the MTD of ixazomib for the three regimens which it was unknown for was not found due to the nature of the data distribution. CONCLUSION: The results indicated that ixazomib is not an effective replacement for bortezomib or carfilzomib in combination treatments containing these drugs, which is apparent from low primary and secondary efficacy endpoints. However, due to a low occurrence of adverse events, serious adverse events, and dose limiting toxicities safety was confirmed. In addition, physicians should determine the MTD on a case by case basis through individual dose escalations if ixazomib is to be used in this context.

<p dir="ltr">Human babesiosis is a malaria-like, tick-borne infectious disease of major public health importance with a global distribution. Babesiosis is caused by intraerythrocytic, apicomplexan parasites of the genus Babesia. In the United States, human babesiosis is primarily caused by Babesia microti and Babesia duncani. Of these parasites, B. duncani infection is lethal to susceptible patients. Current treatment for babesiosis includes either the synergistic use of atovaquone and azithromycin or the combination of clindamycin and quinine. However, the side effects and the resistance posed by these parasites called for alternative approaches for the treatment of human babesiosis. Parasite-derived proteases play several functions in the context of parasitic lifestyle and regulate basic biological processes including cell death, cell progression and cell migration. We hypothesized that proteases are promising class of drug targets in Babesia parasites. Using the SYBR-Green assay, we screened a protease inhibitor library consists of 160 compounds against B. duncani in vitro culture at 50µM and identified 13 preliminary hits. Additionally, dose response assays of hit compounds against <i>B. duncani</i> and <i>B. microti</i> in vitro cultures identified 5 compounds as effective inhibitors against parasite growth. Of these 5 compounds, we chose ixazomib, a proteasome inhibitor as a potential drug for further studies based on its lower IC50 of 58nM as well as a higher therapeutic index as compared to other hit compounds. We demonstrated that in a mouse model infected with <i>target,</i>, the most effective inhibitor, the prodrug of ixazomib at a low dose of 2.5mg/kg lowers parasite proliferation without causing any adverse effects in animals. Thus, our studies suggest that Babesia proteasome may be an important drug target, and ixazomib may be a potential compound that may be used for the treatment of human babesiosis.</p>