A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors

Abstract

Background: The 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.

Methods: This 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.

Results: A 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.

Conclusions: The 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 registration: ClinicalTrials.gov NCT00600496; registered 8 July 2009.

Keywords: Advanced solid tumors; Dacarbazine; Docetaxel; Dose-escalation; Selumetinib.

Figures

Fig. 1

Patient disposition at the time of data cut-off for primary safety analysis (August 2010) in the (a) selumetinib plus docetaxel and (b) selumetinib plus dacarbazine treatment arms. BID, twice daily; ppG-CSF, primary prophylactic granulocyte-colony stimulating factor

Fig. 2

Waterfall plots for greatest change in target lesion size from baseline for the (a) selumetinib plus docetaxel and (b) selumetinib plus dacarbazine arms. Lower reference line indicates the point below which best response is partial response (>30% reduction). Upper reference line indicates the point above which best response is progressive disease (>20%). Administration of primary prophylactic granulocyte colony stimulating factor (ppG-CSF) differed between the part A selumetinib 75 mg bid cohort due to differences in treatment practices between study centers: aReceived primary ppG-CSF in cycle 1; bDid not receive ppG-CSF in cycle 1. Response Evaluation Criteria In Solid Tumors best response: N, not evaluable; P, progressive disease; R, partial response; S, stable disease. Population: Measurable disease at baseline and underwent follow-up scan