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10.1093/annonc/mdw282

http://scihub22266oqcxt.onion/10.1093/annonc/mdw282
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suck abstract from ncbi


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pmid27672108
      Ann+Oncol 2016 ; 27 (10 ): 1928-40
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  • First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin s lymphomas #MMPMID27672108
  • Patnaik A ; Appleman LJ ; Tolcher AW ; Papadopoulos KP ; Beeram M ; Rasco DW ; Weiss GJ ; Sachdev JC ; Chadha M ; Fulk M ; Ejadi S ; Mountz JM ; Lotze MT ; Toledo FG ; Chu E ; Jeffers M ; Peņa C ; Xia C ; Reif S ; Genvresse I ; Ramanathan RK
  • Ann Oncol 2016[Oct]; 27 (10 ): 1928-40 PMID27672108 show ga
  • BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.
  • |Administration, Intravenous [MESH]
  • |Adult [MESH]
  • |Aged [MESH]
  • |Class I Phosphatidylinositol 3-Kinases/*antagonists & inhibitors/genetics [MESH]
  • |Dose-Response Relationship, Drug [MESH]
  • |Enzyme Inhibitors/*administration & dosage/adverse effects/pharmacokinetics [MESH]
  • |Female [MESH]
  • |Humans [MESH]
  • |Lymphoma, Non-Hodgkin/*drug therapy/enzymology/pathology [MESH]
  • |Male [MESH]
  • |Middle Aged [MESH]
  • |Neoplasm Staging [MESH]
  • |Neoplasms/*drug therapy/enzymology/pathology [MESH]
  • |Pyrimidines/*administration & dosage/adverse effects/pharmacokinetics [MESH]


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