High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury. This article provides comprehensive recommendations for prevention of toxicity from HDMTX, along with detailed treatment guidance to mitigate acute kidney injury and subsequent toxicity.

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities. ABSTRACTpression including thrombocytopenia, and dose-limiting peripheral neuropathy (PN) (up to 30% Grade 1/2 and 7-15% Grade 3/4). The PN often leads to discontinuation, and can be debilitating and occasionally irreversible. [19][20][21] Thalidomide is even more strongly implicated in PN, 22 and a recent analysis of patients with newly diagnosed MM revealed that although thalidomide improved efficacy when added to melphalan-prednisone, it negatively impacted safety. 23 Maintenance therapy, as well as consolidation strategies, with many of these drugs are being investigated as important ways to improve and prolong responses in patients with MM, 24 and these extended treatment periods may draw increased attention to tolerability and cumulative toxicities when considering longterm treatment options.Carfilzomib was initially evaluated in 2 phase I studies 25 and PX-171-002 26) investigating two different dosing schedules: 5 consecutive days of a 14-day cycle and 2 consecutive days/week for 3 weeks of a 28-day cycle). Consecutive day dosing demonstrated promising antitumor activity. However, single-agent carfilzomib administered using the 2 consecutive day dosing schedule (PX-171-002) was better tolerated and was chosen for further exploration in ph...

Key Points Twice-weekly oral ixazomib appears tolerable, with no severe neuropathy seen to date, in heavily pretreated multiple myeloma patients. These phase 1 data suggest clinical activity including 76% stable disease or better, with durable responses and sustained disease control.

The coronavirus disease 2019 (COVID-19) pandemic has disrupted all aspects of clinical care, including cancer clinical trials. In March 2020, ASCO launched a survey of clinical programs represented on its Cancer Research Committee and Research Community Forum Steering Group and taskforces to learn about the types of changes and challenges that clinical trial programs were experiencing early in the pandemic. There were 32 survey respondents; 14 represented academic programs, and 18 represented community-based programs. Respondents indicated that COVID-19 is leading programs to halt or prioritize screening and/or enrollment for certain clinical trials and cease research-only visits. Most reported conducting remote patient care where possible and remote visits and monitoring with sponsors and/or contract research organizations (CROs); respondents viewed this shift positively. Numerous challenges with conducting clinical trials were reported, including enrollment and protocol adherence difficulties with decreased patient visits, staffing constraints, and limited availability of ancillary services. Interactions with sponsors and CROs about modifying trial procedures were also challenging. The changes in clinical trial procedures identified by the survey could serve as strategies for other programs attempting to maintain their clinical trial portfolios during the COVID-19 pandemic. Additionally, many of the adaptations to trials made during the pandemic provide a long-term opportunity to improve and transform the clinical trial system. Specific improvements could be expanded use of more pragmatic or streamlined trial designs, fewer clinical trial–related patient visits, and minimized sponsor and CRO visits to trial programs.

Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 lM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.Metastatic disease is the major cause of death in almost all cancer types; however, most treatments are developed to target the primary tumor and not the metastases. This is due to metastatic cells being difficult to detect, highly aggressive, chemoresistant and experimentally challenging to model. 1 At present, there is no agent in clinical use that effectively prevents metastasis and most patients ultimately succumb to metastatic disease.The metastatic process can be broadly categorized into three stages-tumor cell invasion into surrounding tissue, intravasation into blood or lymphatic vessels and extravasation into a new host environment. These events are triggered by genetic and epigenetic alterations that transform stationary epithelial cells into migratory cells, a process termed epithelialmesenchymal transition (EMT). 2,3 Recent data suggests that cancer cells can re-trigger EMT to migrate into surrounding tissue. 3,4 A classical EMT protein is vimentin; numerous reports show that vimentin is overexpressed in invasive human tumors but is nearly undetectable in non-invasive, stationary tumors. 3,[5][6][7] Vimentin is a Type III intermediate filament 8 and its overexpression correlates with metastatic disease, EMT induction, poor prognosis and reduced patient survival. 7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer ce...