A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies

Trisha M. Wise-Draper, Ganesh Moorthy, Mohamad A. Salkeni, Nagla Abdel Karim, Hala Elnakat Thomas, Carol A. Mercer, M. Shalaan Beg, Sue O’Gara, Olugbenga Olowokure, Hassana Fathallah, Sara C. Kozma, George Thomas, Olivier Rixe, Pankaj Desai, John C. Morris

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. Objective: To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. Patients and Methods: BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. Results: Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. Conclusions: The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug–drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104[Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)323-332
Number of pages10
JournalTargeted Oncology
Volume12
Issue number3
DOIs
StatePublished - Jun 1 2017

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Phosphatidylinositol 3-Kinases
Pharmacokinetics
Neoplasms
Mucositis
Everolimus
dactolisib
Nausea
Biological Availability
Fatigue
Diarrhea
Safety
Liver
Enzymes
Pharmaceutical Preparations
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Wise-Draper, T. M., Moorthy, G., Salkeni, M. A., Karim, N. A., Thomas, H. E., Mercer, C. A., ... Morris, J. C. (2017). A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. Targeted Oncology, 12(3), 323-332. https://doi.org/10.1007/s11523-017-0482-9

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. / Wise-Draper, Trisha M.; Moorthy, Ganesh; Salkeni, Mohamad A.; Karim, Nagla Abdel; Thomas, Hala Elnakat; Mercer, Carol A.; Beg, M. Shalaan; O’Gara, Sue; Olowokure, Olugbenga; Fathallah, Hassana; Kozma, Sara C.; Thomas, George; Rixe, Olivier; Desai, Pankaj; Morris, John C.

In: Targeted Oncology, Vol. 12, No. 3, 01.06.2017, p. 323-332.

Research output: Contribution to journalArticle

Wise-Draper, TM, Moorthy, G, Salkeni, MA, Karim, NA, Thomas, HE, Mercer, CA, Beg, MS, O’Gara, S, Olowokure, O, Fathallah, H, Kozma, SC, Thomas, G, Rixe, O, Desai, P & Morris, JC 2017, 'A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies', Targeted Oncology, vol. 12, no. 3, pp. 323-332. https://doi.org/10.1007/s11523-017-0482-9
Wise-Draper, Trisha M. ; Moorthy, Ganesh ; Salkeni, Mohamad A. ; Karim, Nagla Abdel ; Thomas, Hala Elnakat ; Mercer, Carol A. ; Beg, M. Shalaan ; O’Gara, Sue ; Olowokure, Olugbenga ; Fathallah, Hassana ; Kozma, Sara C. ; Thomas, George ; Rixe, Olivier ; Desai, Pankaj ; Morris, John C. / A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. In: Targeted Oncology. 2017 ; Vol. 12, No. 3. pp. 323-332.
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AU - Moorthy, Ganesh

AU - Salkeni, Mohamad A.

AU - Karim, Nagla Abdel

AU - Thomas, Hala Elnakat

AU - Mercer, Carol A.

AU - Beg, M. Shalaan

AU - O’Gara, Sue

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AU - Fathallah, Hassana

AU - Kozma, Sara C.

AU - Thomas, George

AU - Rixe, Olivier

AU - Desai, Pankaj

AU - Morris, John C.

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N2 - Background: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. Objective: To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. Patients and Methods: BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. Results: Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. Conclusions: The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug–drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104[Figure not available: see fulltext.].

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