A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose‐escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50–350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half‐life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition.

Mitochondrial ribosomes in cancer

“…Furthermore, treatment of 20 primary acute myeloid leukemia (AML) cell lines with tigecycline for 48 hrs selectively killed leukemia stem and progenitor cells with efficacy similar to EF-Tu silencing [129]. Preclinical efficacy and safety of tigecycline have been tested in patients with relapsed and refractory AML, but none of the patients had a clinical response in a phase I study of escalating tigecycline doses [154]. …”

Mitochondria in cancer metabolism, an organelle whose time has come?

“…Since the toxicology and pharmacology is already known in humans this can lead to rapid advancement into clinical trials. A phase I trial in relapsed or refractory acute myeloid leukemia was conducted and the MTD in this population was established [54]. Unfortunately, no clinical responses were observed in this trial.…”

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

“…These results, together with the fact that tigecycline has already been approved by the FDA, point to the combination of tigecycline and imatinib as a suitable clinical approach to eliminate disease persistence in CML patients. However, results from an already conducted phase I clinical trial with tigecycline in AML patients were discouraging , as no significant clinical response was observed in any of the patients at the end of the trial. Tigecycline treatment did not affect the expression of mitochondrial‐encoded proteins in 24 of 27 patients, indicating that the concentration achieved in AML patients was not sufficient to be effective and hit its target.…”