In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.
The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.
Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839
PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
The addition of erlotinib to bevacizumab significantly improved PFS but not OS. Although generally well tolerated, the modest impact on survival and increased toxicity associated with the addition of erlotinib to bevacizumab maintenance mean that this two-drug maintenance regimen will not lead to a new postchemotherapy standard of care.
BACKGROUNDPyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODSIn this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTSCommon adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONSThe administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.
INTRODUCTION: Somatic IDH1/2 mutations occur in multiple solid and hematologic tumors, including acute myeloid leukemia. Mutant IDH1/2 proteins have novel enzymatic activity, catalyzing the reduction of α-ketoglutarate to produce the oncometabolite, D-2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes including impaired cellular differentiation. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of the mutated IDH1 protein, and has been shown to lower 2-HG levels and restore cellular differentiation in IDH1-mutant primary human blast cells cultured ex vivo. AG-120 is currently being assessed in a first-in-human, phase 1 study enrolling patients with IDH1-mutant, advanced hematologic malignancies (NCT02074839). Our objective was to further assess the longitudinal pharmacokinetic/pharmacodynamic (PK/PD) data from the ongoing phase 1 study, including dose proportionality assessment of AG-120 exposure after single and multiple doses over time, and the influence of patient-intrinsic factors. METHODS: The AG-120 phase 1, open-label, dose-escalation and expansion study includes evaluation of safety, tolerability, maximum tolerated dose, PK/PD (including 2-HG levels) and clinical activity. Single-agent AG-120 is administered orally once (QD) or twice (BID) daily in continuous 28-day cycles. Patients included in this analysis received doses of 100 mg BID, 300 mg QD, 500 mg QD, 800 mg QD and 1200 mg QD (N=39). Blood, bone marrow and urine samples were collected at multiple time points for determination of PK/PD using qualified LC-MS/MS-based methods. Analyses were performed using WinNonLin®. RESULTS: AG-120 exposure exceeding the predicted efficacious exposure level was demonstrated at all dose levels following oral administration. Following both single (Day-3) and multiple (Cycle 1 Day 15 [C1D15] and Cycle 2 Day 1) dose administration, mean plasma exposures of AG-120 increased less than proportionally to dose, although plasma exposures were quite variable within dose levels. Preliminary PK data revealed a mean half-life of 119 ± 104 hr. Following multiple doses, most patients achieved steady state in Cycle 1, with ~2 to 3-fold accumulation in plasma observed. Furthermore, pre-dose AG-120 trough levels were maintained above the predicted efficacious exposure level throughout treatment (up to 11 cycles). Following a single dose of AG-120, plasma 2-HG levels gradually reduced over 3 days. After multiple doses, plasma 2-HG levels were reduced to levels seen in healthy volunteers (up to 99.7% inhibition) at all dose levels tested. Steady state 2-HG inhibition was reached at approximately C1D15 in most patients, and was maintained over the course of treatment (up to 11 cycles). Mean bone marrow 2-HG levels were also substantially reduced following multiple doses of AG-120 at all dose levels tested (up to 99.9% reduction compared with baseline). Plasma 2-HG levels showed a positive correlation with levels in bone marrow (r2=0.882, p<0.001) and urine (r2=0.528, p<0.001), with a stronger correlation being observed with the former tissue. There was no clear effect of patient-intrinsic factors such as body weight or body surface area on Cmaxor AUC within the ranges tested, although the current sample size is small. Population PK and PK/PD assessments will be conducted to confirm these findings. These analyses are based on data as of 1 May 2015; updated analyses will be presented. CONCLUSION: AG-120 exposure increased less than proportionally to dose following oral administration, with long half-life and maintenance of pre-dose levels above the predicted efficacious exposure, supporting QD dosing. In patients with IDH1 mutations, AG-120 inhibited plasma 2-HG to within levels found in healthy volunteers, and also inhibited 2-HG in bone marrow. Disclosures Fan: Agios Pharmaceuticals: Employment, Equity Ownership. Le:Agios Pharmceuticals: Employment, Equity Ownership. Manyak:Agios Pharmaceuticals: Employment. Liu:Agios: Employment. Prahl:Agios Pharmaceuticals: Employment, Equity Ownership. Bowden:Agios Pharmaceuticals: Employment. Biller:Agios Pharmaceuticals: Employment, Equity Ownership; Arbutus BioPharma (formerly Tekmira): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Arvinas: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Denali: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Agresta:Agios: Employment, Equity Ownership. Yang:Agios Pharmaceuticals: Employment, Equity Ownership.
R1507 added to six standard oncology regimens was well tolerated with an ORR of 36 %.
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