Abstract
BackgroundThe RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors.MethodsThis study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m2 or dacarbazine 1000 mg/m2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A.ResultsA total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine.ConclusionsThe combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors.Trial registrationClinicalTrials.gov NCT00600496; registered 8 July 2009.
Highlights
The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers
The potential benefit of combining MEK inhibitors with chemotherapy has been demonstrated in preclinical studies of tumor xenograft models, in which selumetinib in combination with cytotoxic agents, such as docetaxel or the dacarbazine derivative temozolomide, showed enhanced tumor growth inhibition compared with selumetinib monotherapy, or chemotherapy alone [1, 11]
In consideration of the notable differences in safety and tolerability profiles when combining selumetinib with different classes of cancer therapeutics, we present here data from 60 patients who received selumetinib in combination with cytotoxic agents
Summary
Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and highly selective, allosteric MEK1/2 inhibitor [3] with a short half-life [4, 5]. The potential benefit of combining MEK inhibitors with chemotherapy has been demonstrated in preclinical studies of tumor xenograft models, in which selumetinib in combination with cytotoxic agents, such as docetaxel or the dacarbazine derivative temozolomide, showed enhanced tumor growth inhibition compared with selumetinib monotherapy, or chemotherapy alone [1, 11]. We present the phase I study on which development of these combinations was based
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