Purpose: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. Experimental Design: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. Results: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mgonce daily. A plateauin steady-state exposure was observedat doses of z800 mg once daily.The mean elimination half-life at this dose was 31.1hours. A mean target trough concentration (C 24 ) z15 Ag/mL (34 Amol/L) was achieved at 800 mg once daily.Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of z6 months was observedin 14 patients; clinical benefit was generally observed in patients who received doses of z800 mg once daily or 300 mg twice daily. Conclusion: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.

Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia () gene rearrangements () resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.

Background:Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC).Methods:Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries.Results:Strong correlation between increased blood pressure and Cτ was observed (r2=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r2=0.27). Cτ threshold of >20.5 μg ml−1 was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml−1. However, the association of Cτ with certain adverse events, particularly hand–foot syndrome, was continuous over the entire Cτ range.Conclusions:The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.