Intermittent dosing in melanoma.
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ABSTRACT:
SUBMITTER: McMahon M
PROVIDER: S-EPMC4839533 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
Publications
Intermittent dosing in melanoma.
Clinical advances in hematology & oncology : H&O 20150601 6
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Project description:IntroductionIntermittent dosing (ID), in which periods of stimulation-on are alternated with periods of stimulation-off, is generally employed using 30 sec ON and 90 sec OFF intervals with burst spinal cord stimulation (SCS). The goal of this study was to evaluate the feasibility of using extended stimulation-off periods in patients with chronic intractable pain.Materials and methodsThis prospective, multicenter, feasibility trial evaluated the clinical efficacy of the following ID stimulation-off times: 90, 120, 150, and 360 sec with burst waveform parameters. After a successful trial (≥50% pain relief) using ID stimulation, subjects were titrated with OFF times beginning with 360 sec. Pain, quality of life, disability, and pain catastrophizing were evaluated at one, three, and six months after permanent implant.ResultsFifty subjects completed an SCS trial using ID stimulation settings of 30 sec ON and 90 sec OFF, with 38 (76%) receiving ≥50% pain relief. Pain scores were significantly reduced from baseline at all time points (p < 0.001). Improvements in quality of life, disability, and pain catastrophizing were aligned with pain relief outcomes; 45.8% of the subjects that completed the six-month follow-up visit used an OFF period of 360 seconds.ConclusionsID burst SCS effectively relieved pain for six months. The largest group of subjects used IDB settings of 30 sec ON and 360 sec OFF. These findings present intriguing implications for the optimal "dose" of electricity in SCS and may offer many advantages such as optimizing the therapeutic window, extending battery life, reducing recharge burden and, potentially, mitigating therapy habituation or tolerance.
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Project description:EGF receptor (EGFR) inhibitors are used in the therapy of lung and pancreatic cancers and effectively prevent cancers in multiple animal models. Although daily dosing with erlotinib is effective, weekly dosing may reduce toxicity and have advantages, particularly for prevention. We tested alternative dosing regimens for preventive/therapeutic efficacy in a rat mammary cancer model. For prevention, erlotinib was administered by gavage beginning 5 days after methylnitrosourea (MNU). For therapy and biomarker studies, rats with palpable mammary cancers were treated for six weeks or for six days, respectively. Experiment A, erlotinib (6 mg/kg body weight/day, intragastric): daily (7 times/week); one day on/one day off; and two days on/two days off. All regimens decreased tumor incidence, increased tumor latency, and decreased cancer multiplicity versus controls (P < 0.01). However, intermittent dosing was less effective than daily dosing (P < 0.05). Experiment B, erlotinib (6 mg/kg body weight/day) daily or two days on/two days off or one time per week at 42 mg/kg body weight. All regimens reduced cancer incidence and multiplicity versus controls (P < 0.01). Interestingly, daily and weekly dosing were equally effective (P > 0.5). Experiment C, erlotinib administered at 42 or 21 mg/kg body weight 1 time per week, decreased tumor incidence and multiplicity (P < 0.01). Erlotinib had a serum half-life of ≤ 8 hours and weekly treatment yielded effective serum levels for ≤ 48 hours. Daily or weekly treatment of cancer bearing rats reduced mammary tumor size 25% to 35%, whereas control cancers increased >250%. Levels of phosphorylated extracellular signal-regulated kinase (ERK) were strongly decreased in rats treated daily/weekly with erlotinib. Thus, altering the dose of erlotinib retained most of its preventive and therapeutic efficacy, and based on prior clinical studies, is likely to reduce its toxicity.
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Project description:A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.
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Project description:IntroductionUveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity.MethodsWe conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments.Results29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases.ConclusionsWe identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.
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