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A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced
Patricia M LoRusso1, Jeffrey R Infante2,3, Kevin B Kim4
1Yale Cancer Center, PO Box 208028, New Haven, CT, 06520-8028, USA. patricia.lorusso@yale.edu.
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.
Insights
This study found that combining selumetinib with docetaxel or dacarbazine showed manageable safety and preliminary clinical activity in advanced solid tumors. The MEK1/2 inhibitor selumetinib demonstrated potential in these combination therapies.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- The RAS/RAF/MEK/ERK pathway is frequently activated in various cancers.
- Selumetinib is a potent MEK1/2 inhibitor with demonstrated clinical activity in advanced cancers.
- Preclinical studies suggest selumetinib may enhance chemotherapy efficacy.
Purpose of the Study:
- To assess the safety, tolerability, and pharmacokinetics of selumetinib in combination with docetaxel or dacarbazine.
- To determine the maximum tolerated dose (MTD) of selumetinib when combined with these chemotherapeutic agents.
- To evaluate preliminary clinical activity of the combination regimens.
Main Methods:
- Phase I, open-label, multicenter study.
- Dose escalation to determine MTD of selumetinib BID with docetaxel or dacarbazine every 21 days.
- Dose expansion at MTD to further evaluate safety, tolerability, and pharmacokinetics.
Main Results:
- MTD of selumetinib was 75 mg BID with docetaxel or dacarbazine.
- Common adverse events included diarrhea, edema, fatigue, and nausea.
- Partial responses observed in 6/35 patients with selumetinib plus docetaxel and 4/25 with selumetinib plus dacarbazine.
Conclusions:
- Selumetinib combined with docetaxel or dacarbazine demonstrated manageable safety and tolerability.
- Preliminary clinical activity was observed in patients with advanced solid tumors.
- These combinations represent a potential therapeutic strategy for advanced cancers.
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