Cancer Therapy: Clinical A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia Timothy S. Pardee 1,2,3 , Rebecca G. Anderson 1,2 , Kristin M. Pladna 1 , Scott Isom 4 , Lais P. Ghiraldeli 2 , Lance D. Miller 2 , Jeff W. Chou 4,5 , Guangxu Jin 5 , Wei Zhang 2 , Leslie R. Ellis 1 , Dmitriy Berenzon 1 , Dianna S. Howard 1 , David D. Hurd 1 , Megan Manuel 1 , Sarah Dralle 1 , Susan Lyerly 1 , and Bayard L. Powell 1 Abstract Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and a-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemo- therapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia. Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML. Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CRþ5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor- risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signa- ture consistent with the presence of B cells in the pretreatment marrow of responders. Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. Ó2018 AACR. Introduction Acute myeloid leukemia (AML) is characterized by poor out- comes and resistance to therapy. It is the most common acute leukemia in adults affecting approximately 20,000 people per year in the United States; despite decades of research, the overall 5-year survival remains 30%–40% (1). Current therapy is a combination of cytarabine and daunorubicin, first reported in 1973 and not substantially changed since then (2). Therapy results in a 60%–80% remission rate; but over 50% of patients will relapse, and once relapsed most will die from AML within a year (3). Despite the central role of relapse and resistance to therapy, little is known about the mechanisms involved. With the discovery of the role of mutant isocitrate dehydroge- nase in the leukemogenesis of some types of AML, it has become clear that mitochondrial metabolism can have a profound effect (reviewed by Medeiros and colleagues; ref. 4). Despite these studies it is not well understood to what degree AML cells can alter their mitochondrial metabolism in response to environmen- tal stressors, including those induced by chemotherapy. Fatty acid oxidation may support myeloid leukemic stem cell persistence (5), but the role of mitochondrial metabolism in resistance to chemotherapy in AML is poorly understood. A recent elegant study demonstrated that residual, cytarabine-resistant AML cells in the marrow of treated animals had increased oxidative metab- olism and mitochondrial mass suggesting a direct role of mito- chondrial metabolism in resistance to therapy (6). CPI-613 is a novel lipoic acid analogue with anticancer activity that inhibits PDH and KGDH (7, 8). CPI-613 inhibits mitochon- drial respiration, causing hyperphosphorylation of PDH and activation of adenosine monophosphate–activated kinase (AMPK) in AML cell lines (9). In a single-agent phase I study, CPI-613 was well tolerated. The current study sought to establish the role of PDH in resistance to chemotherapy in preclinical models of AML and conducted a phase I clinical trial to determine the safety of CPI-613 plus high-dose cytarabine (HiDAC) and mitoxantrone in patients with relapsed or refractory AML. The role of p53 in response to CPI-613 was also assessed. Finally, RNA 1 Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, North Carolina. 2 Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston- Salem, North Carolina. 3 Rafael Pharmaceuticals Inc, Cranbury, New Jersey. 4 Department of Biostatistical Sciences, Wake Forest Public Health Sciences, Winston-Salem, North Carolina. 5 Biostatistics Core, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, North Carolina. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Timothy S. Pardee, Section on Hematology and Oncol- ogy, Department of Internal Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: 336-716-7970; Fax: 336-716-5687; E-mail: tspardee@wakehealth.edu doi: 10.1158/1078-0432.CCR-17-2282 Ó2018 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 24(9) May 1, 2018 2060 on May 30, 2020. © 2018 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst February 6, 2018; DOI: 10.1158/1078-0432.CCR-17-2282