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
Authors: Gonsalves Wilson I , Kumar Shaji , Perez Gabriela , Saathoff Stephanie , Wilson Diana M , Young Anna , Ailawadhi Sikander 
Published: November 2021

Abstract
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 maximum dose of 2500 mg twice daily. Key inclusion criteria include having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, adequate hematologic reserve, kidney function and liver function. This trial especially allows patients with non-secretory disease yet measurable by bone marrow assessments or cross-sectional imaging of plasmacytomas to be enrolled which constitutes an unmet need in the real-world MM population. Finally, this allows patients to be treated with a dexamethasone-free regimen. The primary objective of this trial is to determine the MTD of metformin and nelfinavir in combination with bortezomib. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated with this combination. Potential predictive biomarkers as well as resistance mechanisms using genomic RNA, immunohistochemistry and metabolomics-based assessment platforms will be evaluated in this study. Recruitment is ongoing with no safety concerns. This trial is registered on clinicaltrials.gov: NCT03829020. This investigator-initiated trial was funded by the generous gift of the Helen Diller Family Foundation.

Disclosures
Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.