A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors

J. E. Grilley-Olson, P. L. Bedard, A. Fasolo, M. Cornfeld, L. Cartee, A. R Abdul Razak, L. A. Stayner, Y. Wu, R. Greenwood, R. Singh, C. B. Lee, J. Bendell, H. A. Burris, G. Del Conte, C. Sessa, J. R. Infante

Research output: Contribution to journalArticle

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Abstract

Summary: Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalInvestigational New Drugs
DOIs
Publication statusAccepted/In press - Jul 23 2016

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Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinases
Neoplasms
Maximum Tolerated Dose
Pharmacokinetics
trametinib
2,4-difluoro-N-(2-(methyloxy)-5-(4-(4-pyridazinyl)-6-quinolinyl)-3-pyridinyl)benzenesulfonamide
Exanthema
Diarrhea
Biomarkers
Safety
Skin
Mutation
DNA

Keywords

  • GSK2126458
  • MEK inhibitor
  • Phase I clinical trial
  • PI3K inhibitor
  • Trametinib

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. / Grilley-Olson, J. E.; Bedard, P. L.; Fasolo, A.; Cornfeld, M.; Cartee, L.; Razak, A. R Abdul; Stayner, L. A.; Wu, Y.; Greenwood, R.; Singh, R.; Lee, C. B.; Bendell, J.; Burris, H. A.; Del Conte, G.; Sessa, C.; Infante, J. R.

In: Investigational New Drugs, 23.07.2016, p. 1-10.

Research output: Contribution to journalArticle

Grilley-Olson, JE, Bedard, PL, Fasolo, A, Cornfeld, M, Cartee, L, Razak, ARA, Stayner, LA, Wu, Y, Greenwood, R, Singh, R, Lee, CB, Bendell, J, Burris, HA, Del Conte, G, Sessa, C & Infante, JR 2016, 'A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors', Investigational New Drugs, pp. 1-10. https://doi.org/10.1007/s10637-016-0377-0
Grilley-Olson, J. E. ; Bedard, P. L. ; Fasolo, A. ; Cornfeld, M. ; Cartee, L. ; Razak, A. R Abdul ; Stayner, L. A. ; Wu, Y. ; Greenwood, R. ; Singh, R. ; Lee, C. B. ; Bendell, J. ; Burris, H. A. ; Del Conte, G. ; Sessa, C. ; Infante, J. R. / A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. In: Investigational New Drugs. 2016 ; pp. 1-10.
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abstract = "Summary: Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 {\%}) and diarrhea (61 {\%}). Dose interruptions due to adverse events occurred in 42 {\%} of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 {\%} of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.",
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T1 - A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors

AU - Grilley-Olson, J. E.

AU - Bedard, P. L.

AU - Fasolo, A.

AU - Cornfeld, M.

AU - Cartee, L.

AU - Razak, A. R Abdul

AU - Stayner, L. A.

AU - Wu, Y.

AU - Greenwood, R.

AU - Singh, R.

AU - Lee, C. B.

AU - Bendell, J.

AU - Burris, H. A.

AU - Del Conte, G.

AU - Sessa, C.

AU - Infante, J. R.

PY - 2016/7/23

Y1 - 2016/7/23

N2 - Summary: Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

AB - Summary: Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

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KW - PI3K inhibitor

KW - Trametinib

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