A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors

  • Carol Aghajanian
  • Katherine M. Bell-McGuinn
  • Howard A. BurrisIII
  • Lillian L. Siu
  • Lee-Ann Stayner
  • Jennifer J. Wheler
  • David S. Hong
  • Carla Kurkjian
  • Shubham Pant
  • Ademi Santiago-Walker
  • Jennifer L. Gauvin
  • Joyce M. Antal
  • Joanna B. Opalinska
  • Shannon R. Morris
  • Jeffrey R. Infante
PHASE I STUDIES
  • 53 Downloads

Summary

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

Keywords

GSK2141795 Akt PIK3 PTEN Endometrial cancer 

Notes

Acknowledgements

Editorial assistance was provided by SciMentum and funded by GlaxoSmithKline.

Investigators performed the human investigations after approval by a local Human Investigations Committee and in accord with an assurance filed with and approved by the Department of Health and Human Services. The investigators obtained informed consent from each participant or each participant’s guardian.

Compliance with ethical standards

Conflicts of interest

C. Aghajanian declares she participated on a Focus Study Steering Committee for Mateon Therapeutics and has served on the Advisory Boards of Clovis, Cerulean Pharma, Bayer, and VentiRx at various time points since July 2015. K. M. Bell-McGuinn declares she is currently an employee and stockholder of Eli Lilly. H. A. Burris III declares he has no conflict of interest. L. L. Siu declares she has received research funding from GlaxoSmithKline. L. Stayner declares she has no conflict of interest. J. J. Wheler declares she has no conflict of interest. D. S. Hong declares he has received research funding from Adaptimmune, Abbvie, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sanko, Eisai, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Eli Lilly, LOXO, Mirati, Merck, Medimmune, Molecular Template, Novartis, Pfizer, and Takeda; D. S. Hong has also received consulting fees from Bayer, Baxter, Guidepoint Global, and Janssen; D. S. Hong has also received travel accommodations from LOXO and Mirna, and has ownership interest in Molecular Match and Oncoresponse. C. Kurkjian declares she has no conflict of interest. S. Pant declares he has no conflict of interest. A. Santiago-Walker declares she has received personal fees from GlaxoSmithKline. J. L. Gauvin declares she has received personal fees and has stock in GlaxoSmithKline. J.M. Antal declares she holds stock in GlaxoSmithKline and is an employee and holds stock in G1 Therapeutics. J.B. Opalinska declares she was an employee and owns stock in GlaxoSmithKline. S.R. Morris declares she was an employee of and has patent interest with GlaxoSmithKline. J.R. Infante declares he is an employee of Johnson & Johnson.

Financial support

This study was funded by GlaxoSmithKline (NCT number: NCT00920257).

Drs. Aghajanian and Bell-McGuinn (while at MSK) are supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Morgensztern D, McLeod HL (2005) PI3K/AKT/Mtor pathway as a target for cancer therapy. Anti-Cancer Drugs 16:797–803CrossRefPubMedGoogle Scholar
  2. 2.
    Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR (2001) AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 61:589–593PubMedGoogle Scholar
  3. 3.
    Bellacosa A, Testa JR, Moore R et al (2004) A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. Cancer Biol Ther 3:268–275CrossRefPubMedGoogle Scholar
  4. 4.
    Altomare DA, Testa JR (2005) Pertubations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464CrossRefPubMedGoogle Scholar
  5. 5.
    DeFeo-Jones D, Barnett SF, Fu S, Hancock PJ, Haskell KM, Leander KR, McAvoy E, Robinson RG, Duggan ME, Lindsley CW, Zhao Z, Huber HE, Jones RE (2005) Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific AKT/PKB family members. Mol Cancer Ther 4:271–279PubMedGoogle Scholar
  6. 6.
    Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA, Rouse MB, Rabindran SK, Heerding DA, Kumar R (2014) Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One 9:e100880CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, Riisnaes R, Pope LL, Heaton SP, Thomas G, Garrett MD, Sullivan DM, de Bono JS, Tolcher AW (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29:4688–4695CrossRefPubMedGoogle Scholar
  8. 8.
    Yap TA, Yan L, Patnaik A, Tunariu N, Biondo A, Fearen I, Papadopoulos KP, Olmos D, Baird R, Delgado L, Tetteh E, Beckman RA, Lupinacci L, Riisnaes R, Decordova S, Heaton SP, Swales K, deSouza NM, Leach MO, Garrett MD, Sullivan DM, de Bono JS, Tolcher AW (2014) Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clin Cancer Res 20:5672–5685CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, Vo ACH, Klucher K, Herbst RS, Eckhardt SG, Peterson S, Hausman DF, Kurzrock R, Jimeno A (2012) A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 18:4173–4182CrossRefPubMedGoogle Scholar
  10. 10.
    Shapiro GI, Rodon J, Bendell C et al (2013) Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 20:233–245CrossRefPubMedGoogle Scholar
  11. 11.
    Spencer A, Yoon S, Harrison SJ et al (2014) The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood 124:2190–2195CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bendell JC, Rodon J, Burris HA et al (2011) Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 30:282–290CrossRefPubMedGoogle Scholar
  13. 13.
    Britten C, Adjei AA, Millham R et al (2014) Phase I study of PF-04691502, a small molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Investig New Drugs 32:510–517CrossRefGoogle Scholar
  14. 14.
    Algazi AP, Esteve-Puig R, Nosrati A, Hinds B, Hobbs-Muthukumar A, Nandoskar P, Ortiz-Urda S, Chapman PB, Daud A (2018) Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. Pigment Cell Melanoma Res 31:110–114CrossRefPubMedGoogle Scholar
  15. 15.
    Shoushtari AN, Kudchadkar RR, Panageas K, et al (2016) A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced uveal melanoma. J Clin Oncol 34(suppl):Abstract 9511Google Scholar
  16. 16.
    Trudel S, Bahlis NJ, Venner CP, et al (2016) Biomarker driven phase II clinical trial of trametinib in relapsed/refractory multiple myeloma with sequential addition of the AKT inhibitor GSK2141795 at time of disease progression to overcome treatment failure: a trial of the Princess Margaret phase II consortium. Blood 128(22):4526 (abstract)Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Carol Aghajanian
    • 1
    • 2
  • Katherine M. Bell-McGuinn
    • 1
    • 2
    • 3
  • Howard A. BurrisIII
    • 4
    • 5
  • Lillian L. Siu
    • 6
  • Lee-Ann Stayner
    • 6
  • Jennifer J. Wheler
    • 7
  • David S. Hong
    • 7
  • Carla Kurkjian
    • 4
    • 8
  • Shubham Pant
    • 4
    • 8
  • Ademi Santiago-Walker
    • 9
    • 10
  • Jennifer L. Gauvin
    • 9
    • 11
  • Joyce M. Antal
    • 9
    • 12
  • Joanna B. Opalinska
    • 9
    • 13
  • Shannon R. Morris
    • 9
    • 12
  • Jeffrey R. Infante
    • 4
    • 5
  1. 1.Gynecologic Medical Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer Center (MSK)New YorkUSA
  2. 2.Department of MedicineWeill Cornell Medical CollegeNew YorkUSA
  3. 3.Eli Lilly and CompanyIndianapolisUSA
  4. 4.Sarah Cannon Research InstituteNashvilleUSA
  5. 5.Tennessee OncologyNashvilleUSA
  6. 6.Princess Margaret Cancer CentreTorontoCanada
  7. 7.The University of Texas MD Anderson Cancer CenterHoustonUSA
  8. 8.Stephenson Cancer CenterUniversity of OklahomaOklahoma CityUSA
  9. 9.GlaxoSmithKlineCollegevilleUSA
  10. 10.JanssenLansdaleUSA
  11. 11.Novartis PharmaceuticalsOrlandaUSA
  12. 12.MedImmuneGaithersburgUSA
  13. 13.Boehringer-IngelheimRidgefieldUSA

Personalised recommendations