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BMC Cancer. 2017 Mar 6;17(1):173. doi: 10.1186/s12885-017-3143-6.

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

Author information

1
Yale Cancer Center, PO Box 208028, New Haven, CT, 06520-8028, USA. patricia.lorusso@yale.edu.
2
Sarah Cannon Research Institute, Nashville, TN, USA.
3
Tennessee Oncology PLLC, Nashville, TN, USA.
4
California Pacific Medical Center, San Francisco, CA, USA.
5
AstraZeneca, Wilmington, DE, USA.
6
AstraZeneca, Macclesfield, UK.
7
Fox Chase Cancer Center, Philadelphia, PA, USA.

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

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