A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors

Abstract

Summary Background MK-5108 is a potent/highly selective Aurora A kinase inhibitor. Methods A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1–2 in 14–21 day cycles either alone (MT; Panel1/n=18; 200 to 1800 mg) or in combination (CT; Panel2/n=17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. Results 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; 3 patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6–13.5 hours across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

“…AURKA inhibition resulted in the induction of apoptosis and cell death, offering a potential therapeutic perspective for this pathology. A recent Phase I study showed a remarkably low toxicity of this compound in patients with solid tumours [134], making of MK-5108 an interesting candidate for future trials.…”

A phase 1 study of AMG 900, an orally administered pan‐aurora kinase inhibitor, in adult patients with acute myeloid leukemia

“…Though antileukemic responses in this single‐agent setting were modest, it is possible that combining tolerable doses of AMG 900 with additional agents that inhibit cell division through other mechanisms may produce more profound effects. Preclinical data suggest AMG 900 enhances the effect of microtubule‐targeting agents such as paclitaxel, carboplatin, and doxorubicin and this approach is supported by data from combination therapy with other aurora kinase inhibitors . Evaluation of AMG 900 in combination with other agents is an appropriate next step in the development of this molecule as a treatment for AML.…”

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

“…Together with cell biological evidence that inhibition of AurA compromises mitotic progression, an increased AurA expression profile in cancer supports that AurA is a clinically relevant drug target (48). Pharmaceutical companies have begun to exploit this possibility, bringing numerous targeted inhibitors to the market as anti-cancer drugs, and spurring clinical trials (37,(49)(50)(51)(52)(53)(54)(55). However, while the efficacy and safety of inhibiting AurA have been supported by preclinical and early stage clinical trials, response to AurA inhibition has been limited (37, 55-57) and it remains unclear which patients may best benefit from AurA inhibitor treatment either alone, or in combination with standard chemotherapeutic approaches.…”