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AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors.

ABSTRACT: AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors.Thirty-eight patients with advanced malignancies were treated at doses of 10-70 mg once daily (QD) and 20-45 mg b.i.d.Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with minimal accumulation after repeated QD or b.i.d. dosing. Exposure increased in a dose-dependent manner from 10-50 mg. Maximum plasma concentration (Cmax) was attained ?1 hour after dose, and t1/2 was ?5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1-2 hours after dose, coincident with Cmax, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the highest dose tested, 70 mg QD, was 56% (standard deviation: ±21%) at steady-state drug levels. Dose-limiting toxicities (DLTs) consisted of pleiotropic neurologic adverse events (AEs), including dizziness, anxiety, ataxia, memory loss, hallucinations, and behavior changes. These AEs were generally reversible with dose reduction or treatment cessation.Whether the DLTs were due to inhibition of JAK-1/2 or to off-target effects is unknown. The unusual DLTs and the lack of clinical activity led to discontinuation of development.

SUBMITTER: Plimack ER

PROVIDER: S-EPMC3720635 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors.

Plimack Elizabeth R ER Lorusso Patricia M PM McCoon Patricia P Tang Weifeng W Krebs Annetta D AD Curt Gregory G Eckhardt S Gail SG

The oncologist 20130711 7

<h4>Background</h4>AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors.<h4>Methods</h4>Thirty-eight patients with advanced malignancies were treated at doses of 10-70 mg once daily (QD) and 20-45 mg b.i.d.<h4>Results</h4>Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with ...[more]

PMID: 23847256

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Project description:BackgroundAST1306 is an orally active irreversible small molecule inhibitor of EGFR (erbB1), HER2 (erbB2) and HER4 (erbB4) signaling. This is a phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306. In addition the effects of food on PK was tested.MethodsA modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles.ResultsSeventy-one patients were enrolled, with breast (n?=?22) and lung cancers (n?=?14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n?=?1), 1500 mg BID (n?=?1), 800 mg TID (n?=?1) and 1200 mg TID (n?=?2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean T(max) was prolonged, C(max) was increased, and AUC(0-?) was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for???6 months was achieved in 7 patients.ConclusionsBased on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.

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AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors.

Publications

AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors.

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