The Mitochondrial Metabolism Inhibitor Cpi-613 in Combination with High Dose Ara-C (HDAC) and Mitoxantrone Is Highly Active in Poor Risk Relapsed or Refractory Acute Myeloid Leukemia (AML)
Authors: Pardee Timothy , Pladna Kristin , Isom Scott , Ellis Leslie Renee , Berenzon Dmitriy , Howard Dianna , Manuel Megan , Dralle Sarah , Hurd David D , Lyerly Susan , Powell Bayard L 
Published: October 2019

Background: CPI-613 is a first in class agent that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase. As a single agent CPI-613 was found to be well tolerated with possible activity in several patients with myeloid malignancies.This trial determined the maximum tolerated dose (MTD), safety, and efficacy of CPI-613 in combination with HDAC and mitoxantrone in patients with relapsed or refractory AML.

Methods: CPI-613 was given daily on days 1 through 5 starting at a dose of 500 mg/m2. Beginning on day 3, HDAC at 3,000 mg/m2 (or 1,500 mg/m2 for age ≥60) is administered every 12 hours for 5 total doses and mitoxantrone at 6 mg/m2 is given daily for 3 doses. If residual disease is present on day 14 re-induction with the same or a three day abbreviated course could be given. Patients who achieved a complete remission with or without complete count recovery (CR or CRi) could receive up to a total of two additional consolidation cycles with the goal to get responders to stem cell transplant whenever possible.

Results: A total of 67 patients have been enrolled and 65 are evaluable. The median age is 60 (range 21-79). Nineteen patients had refractory disease and 14 received at least 1 previous line of salvage therapy. In patients with relapsed disease the median duration of CR1 was 5 months. Cytogenetics were poor risk in 30 patients, intermediate in 30 and good in 6. One patient had CML in myeloid blast crisis. The overall intention to treat response rate was 48% (26CR+5CRi) with a median survival of 6.4 months. In patients ≥60 years old the CR/CRi rate was 42% (15/36). Surprisingly, the response rate for patients with poor risk cytogenetics was 47% (11CR+3CRi) with a median survival of 5.2 months. In a historical cohort treated with HDAC, mitoxantrone and asparaginase at our institution, only 19% (3/16) of patients with poor risk cytogenetics responded with a median survival of 2.8 months. The MTD of CPI-613 in combination with HDAC and mitoxantrone is 2,500 mg/m2. The dose limiting toxicities were diarrhea and nausea. Nine patients (13%) died on or before day 30. The most common toxicities attributed to CPI-613 were diarrhea and nausea, mainly grade 1 or 2. At the time of this submission thirteen patients have gone on to allogeneic stem cell transplantation. Several patients with circulating blasts had blood samples taken before and after CPI-613 infusion. Three of these patients had increased phosphorylation of PDH consistent with its inhibition. Additionally, two patients demonstrated a robust phosphorylation of adenosine monophosphate-activated protein kinase consistent with depletion of ATP. To explore if loss of p53 function (common in poor risk cytogenetics) affected response we tested CPI-613 alone or with an anthracycline against an AML cell line with and without p53 knockdown. Suppression of p53 function resulted in significant resistance to the anthracycline but no change in response to CPI-613; the combination enhanced cell kill over either agent alone.

Conclusions: CPI-613 in combination with HDAC and mitoxantrone is a promising salvage regimen, especially in patients with poor risk cytogenetics.

Disclosures

Pardee: Novartis: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: CPI-613 is a novel anticancer agent not currently approved by the FDA. Ellis:Alexion: Speakers Bureau. Manuel:Novartis: Speakers Bureau. Hurd:Merck: Equity Ownership; Pfizer: Equity Ownership; Medtronic: Equity Ownership; Procter and Gamble: Equity Ownership; Bristol Myers Squib: Equity Ownership. Powell:Celgene: Speakers Bureau; Cornerstone Pharmaceuticals: Consultancy.