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Phase I Study of Glesatinib (MGCD265) in Combination with Erlotinib or Docetaxel in Patients with Advanced Solid
Amita Patnaik1, Shirish Gadgeel2,3, Kyriakos P Papadopoulos4
1START, 4383 Medical Drive, Suite 4026, San Antonio, TX, 78229, USA. amita.patnaik@startsa.com.
Background:
Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL.
Objective:
This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel.
Patients And Methods:
The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/m2) were administered with erlotinib or docetaxel (starting doses 100 mg once daily and 50 mg/m2, respectively) using a modified 3 + 3 design. Maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLTs) during the first 21-day treatment cycle. Enrollment focused on patients with solid tumor types typically associated with MET aberration and/or AXL overexpression. The primary objective was to determine the safety profile of the treatment combinations. Antitumor activity and pharmacokinetics (PK) were also assessed.
Results:
Ten dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/m2 plus docetaxel exceeded the MTD. Further dosing focused on glesatinib micronized V2: maximum administered dose (MAD) was 700 mg twice daily with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks. DLTs, acceptable at lower glesatinib (micronized V2) dose levels, occurred in two of five and two of six patients at the MADs of glesatinib + erlotinib and glesatinib + docetaxel, respectively. Across all cohorts, the most frequent treatment-related adverse events were diarrhea (glesatinib + erlotinib: 84.1%; glesatinib + docetaxel: 45.6%), fatigue (46.4%, 70.4%), and nausea (30.4%, 35.1%). The objective response rate was 1.8% and 12.0% in all glesatinib + erlotinib and glesatinib + docetaxel cohorts, respectively.
Conclusions:
The safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors.
Clinical Trials Registration:
ClinicalTrials.gov NCT00975767; 11 September 2009.
Insights
This study evaluated glesatinib combined with erlotinib or docetaxel in solid tumors. The combinations showed acceptable safety and modest efficacy signals in advanced cancers.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Aberrant activation of mesenchymal epithelial transition factor (MET) and AXL are common oncogenic drivers in solid tumors.
- Glesatinib is a multitargeted receptor tyrosine kinase inhibitor targeting MET and AXL.
Purpose of the Study:
- To investigate the safety and antitumor activity of glesatinib in combination with erlotinib or docetaxel.
- To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the combination therapies.
Main Methods:
- Phase I, open-label, multicenter study with two parallel arms.
- Ascending doses of oral glesatinib with erlotinib or docetaxel using a modified 3+3 design.
- Enrollment of patients with solid tumors associated with MET aberration and/or AXL overexpression.
Main Results:
- MTDs were not reached for unmicronized glesatinib plus erlotinib/docetaxel or micronized glesatinib plus erlotinib.
- Micronized glesatinib plus docetaxel exceeded MTD; further studies used glesatinib micronized V2.
- Most frequent adverse events included diarrhea, fatigue, and nausea; objective response rates were 1.8% (erlotinib) and 12.0% (docetaxel).
Conclusions:
- Glesatinib in combination with erlotinib or docetaxel demonstrated an acceptable safety profile with no pharmacokinetic interactions.
- Maximum administered doses of glesatinib (micronized V2) with erlotinib or docetaxel slightly exceeded MTD.
- Modest efficacy signals were observed in non-genetically selected patients with advanced solid tumors.
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