title: A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies.
abstract: OBJECTIVE
  The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the MTD, pharmacokinetics, and safety in patients with relapsed or refractory hematologic malignancies.
  
  
  METHODS
  Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
  
  
  RESULTS
  CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3,780 mg/m(2), there were two dose-limiting toxicities (DLT). At a dose of 2,940 mg/m(2) over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of approximately 1.34 hours. Of the 21 evaluable, heavily pretreated patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation.
  
  
  CONCLUSIONS
  CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients.
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina. Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina. tspardee@wakehealth.edu.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Pardee
authors.affiliation: Cornerstone Pharmaceuticals Inc, Cranbury, New Jersey.
authors.forename: King
authors.initials: K
authors.lastname: Lee
authors.affiliation: Cornerstone Pharmaceuticals Inc, Cranbury, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Luddy
authors.affiliation: Cornerstone Pharmaceuticals Inc, Cranbury, New Jersey.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maturo
authors.affiliation: Cornerstone Pharmaceuticals Inc, Cranbury, New Jersey.
authors.forename: Robert
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Scott
authors.initials: S
authors.lastname: Isom
authors.affiliation: Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Stadelman
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Denise
authors.initials: D
authors.lastname: Levitan
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Hurd
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Ellis
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Robin
authors.initials: R
authors.lastname: Harrelson
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Megan
authors.initials: M
authors.lastname: Manuel
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dralle
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Susan
authors.initials: S
authors.lastname: Lyerly
authors.affiliation: Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina.
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002210:Caprylates / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002210:Caprylates; D013440:Sulfides; C568850:devimistat