Background:
To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.
Methods:
Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg
−1
in combination with fixed doses of pemetrexed (500 mg m
−2
) plus cisplatin (75 mg m
−2
) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.
Results:
Eighteen patients were enrolled. One patient dosed at 4 mg kg
−1
experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg
−1
cohort or the 6 mg kg
−1
dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ⩾3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.
Conclusion:
The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg
−1
, to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.
We describe a pediatric patient with acute leukemia who developed an uncommon but significant metabolic consequence of pegaspargase therapy-severe hypertriglyceridemia (hyperTG). We also relate our experience with continuous insulin infusion treatment for pegaspargase-induced hyperTG. This treatment approach led to a decrease in triglycerides from 4640 mg/dL on admission to 522 mg/dL at discharge 9 days later. Genetic testing revealed that our patient was an apolipoprotein E 3/4 heterozygote. Our review of the literature suggests that apolipoprotein E polymorphism may influence the development of hyperlipidemia in acute lymphoblastic leukemia patients receiving asparaginase therapy and may identify patients at high risk for developing asparaginase-induced hyperTG.
A LSS model to predict AUC(OPZ)/AUC(5OH), and thus CYP2C19 activity, was generated for Caucasian CYP2C19*1/*1 subjects. However, additional model validation is needed prior to general use. LSS models to predict AUC(OPZ)/AUC(SUL), and thus CYP3A activity, were not possible, even upon stratification by CYP2C19 genotype and ethnicity.
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