Trial in Progress: Phase I Open-Label Study of Metformin and Nelfinavir in Combination with Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Background: GLUT4 inhibition is an attractive therapeutic option in multiple myeloma (MM) given the dependence of MM cells on glucose transport. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor in MM cells to counter the possibility of therapeutic resistance to GLUT4 inhibition has demonstrated synergistic promise (Dalva-Aydemir et al, Clin Can Res 2015). Using a GLUT4 inhibitor such as the HIV protease inhibitor nelfinavir is an attractive choice since it not only inhibits the transport function of GLUT4, but it also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (Driessen et al, Blood 2018). Thus, in summary the FDA-approved oral HIV-PI nelfinavir, long used for the treatment of HIV disease, can bind to glucose transporters (GLUT4) on MM cells and reversibly inhibit glucose uptake, thus disrupting the Warburg effect. Nelfinavir can also enhance the activity of PIs such as bortezomib overcome its resistance in MM cells. Metformin, an oral FDA-approved drug for the treatment of Type II Diabetes has the ability to disrupt the electron transport chain of defective mitochondria within MM cells, thus blocking the ability of such mitochondria to generate energy and anabolic substrates as compensatory mechanisms required for proliferation in the setting of GLUT4 inhibition. Thus, this study will look at the safety and tolerability of repurposing the existing FDA-approved drugs for Type II diabetes and HIV in combination with bortezomib for the treatment of relapsed and/or refractory myeloma. Methods: This study is a phase 1 clinical trial of metformin and nelfinavir in combination with bortezomib for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design with 3 dose levels planned. Part B is a dose expansion cohort at the Maximal Tolerated Dose (MTD) determined in Part A. Up to a maximum of 36 patients will be enrolled and treated for a maximum of six 21-day cycles. Bortezomib is administered in its usual weekly subcutaneous dosing schedule of days 1, 8 and 15 of a 21-day cycle at a dose level of 1.3 mg/m2. Metformin will be administered for 14 days of a 21-day cycle and started at a dose level of 500 mg twice daily and will be investigated to a maximum dose of 1000 mg twice daily. Nelfinavir will also be administered for 14 days of a 21-day cycle and started at a dose level of 1250 mg twice daily and will be investigated to a maxi