Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057).

Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non-small-cell lung cancer (NSCLC).

Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors.

Background: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen.

Silent infarcts in young children with sickle cell disease.

Silent infarcts have been reported most commonly in school-aged children with homozygous sickle cell disease (SCD-SS) and are associated with neurocognitive deficits. However, the prevalence of silent infarcts in younger children with SCD-SS is not well defined. In this retrospective study, brain magnetic resonance imaging and angiography (MRI/A) studies performed before 6 years of age in a cohort of children with SCD-SS were analysed and the prevalence of abnormalities was calculated.

Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects.

Dasatinib is a tyrosine kinase inhibitor (including BCR-ABL and the SRC family) that is effective in patients with chronic myeloid leukemia. Dasatinib has pH-dependent solubility and is bioavailable as an oral formulation. The effect of gastric pH modifiers on dasatinib pharmacokinetics is evaluated in an open-label, randomized, 3-period, 3-treatment crossover study.

Importance of characterizing determinants of variability in exposure: application to dasatinib in subjects with chronic myeloid leukemia.

Characterizing the key determinants of variability in the exposure of orally administered drugs may be important in understanding the implications of exposure variability on clinical responses. In particular, partitioning overall variability into interoccasion variability (IOV) and interindividual variability (IIV) allows a better assessment of the clinical importance of exposure variability. The IOV characterizes the dose-to-dose variability in exposure within a subject and is likely to be less clinically relevant than IIV for chronically administered drugs as the effect of IOV averages out over repeated dosing.

Metabolism and disposition of dasatinib after oral administration to humans.

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o.

Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL), a multi-targeted kinase inhibitor.

Purpose: Dasatinib (BMS-354825) is a potent, oral multi-targeted kinase inhibitor. It is an effective therapy for patients with imatinib-resistant or -intolerant Ph+ leukemias,. It has demonstrated promising preclinical anti-tumor activity, and is under clinical evaluation in solid tumors.

Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure.

Purpose: Chronic myeloid leukemia (CML) is caused by reciprocal translocation between chromosomes 9 and 22, forming BCR-ABL, a constitutively activated tyrosine kinase. Imatinib mesylate, a selective inhibitor of BCR-ABL, represents current frontline therapy for CML; however, emerging evidence suggests that drug resistance to imatinib may limit its long-term success. To improve treatment options, dasatinib (BMS-354825) was developed as a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases.

Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma.

Background: Sentinel lymph node (SLN) status is an important prognostic factor for survival for patients with primary cutaneous melanoma. To address the issue of selecting patients at high and low risk for a positive SLN, prognostic factors were sought that predict SLN involvement by examining characteristics of both the primary tumor and the patient within the context of a biological model of melanoma progression.

Methods: The study included 682 patients with primary vertical growth phase (VGP) melanoma and no clinical evidence of metastatic disease who underwent SLN biopsy (1995-2003).

Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.

Background: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL).

Methods: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study.

Prolongation of the prothrombin time and activated partial thromboplastin time in children with sickle cell disease.

Background: Patients with sickle cell disease (SCD) have high rates of perioperative complications, including bleeding 1,2.

Procedures: We conducted a retrospective review of pre-operative coagulation studies in pediatric patients with SCD followed by a prospective study of 100 well children with SCD to determine the prevalence of abnormal coagulation screening tests, and to evaluate potential etiologies.

Results: In the retrospective study, 32/84 (38.