Bisantrene demonstrates clinical response for R/R AML in a phase II clinical trial

On June 16, 2020, positive results of the phase II study of bisantrene (NCT03820908) for patients with relapsed/refractory acute myeloid leukemia (R/R AML) were announced. Bisantrene is an anthracene with anthracycline-like activity that had been demonstrated to be an effective AML salvage drug in the 1980s, with little or no discernible cardiotoxicity. However, it was lost in a series of pharmaceutical mergers. The purpose of this trial was to determine if the current formulation still provides clinical efficacy with modern standards in a cohort of patients with R/R AML that were heavily pretreated. ^1,2

Key features

Bisantrene^1,2

• A small-molecule chemotherapeutic drug, related to anthracyclines but with a greatly reduced risk of cardiotoxicity
• Has the potential to be used for patients who have reached their cardiotoxic limit with anthracyclines or cannot tolerate anthracyclines because of existing heart conditions, age, or other factors
• Shown to have therapeutic efficacy in several cancers, notably AML, from more than 40 published phase II clinical trials in the 1980s and 1990s
• In addition to its cytotoxic effect on proliferating cells, it has been shown to have immunologic and genomic effects
  • Demonstrated to activate macrophages to attack and destroy tumor cells in allogeneic transplant models
  • Binds to DNA at a site that displaces telomerase binding proteins, enabling apoptosis of tumor cells
  • These immune-stimulating and apoptotic mechanisms may make bisantrene highly suitable for use in combination with immunotherapeutic agents

Study design^1,3

• Investigator initiated, open-label, single-agent, phase II trial in ten adult patients with R/R AML who, on average, had failed three prior lines of treatment
• Of the ten patients, seven had relapsed following allogeneic stem cell transplantation, three had an antecedent myeloid disorder, and four had extramedullary disease at the time of recruitment
• Bisantrene was administered at 250 mg/m² per day, for 7 days, in conjunction with the conventional supportive care
• Primary endpoints: Overall survival (OS) and leukemia-free survival at 24 months

Results¹

• One patient achieved complete remission, and three patients achieved a partial remission, resulting in an overall response rate of 40% after a single course of bisantrene treatment
• Of the four patients that responded, all had extramedullary disease
• One patient was bridged to allogeneic stem cell transplantation
• No patients were removed from the study during treatment
• Next generation DNA sequencing of the responding patient samples identified a wide array of genetic mutations, including those associated with activated signaling, splicing, chromatin modification, and epigenetic modification
• The most common Grade 3/4 adverse events were thrombocytopenia (60%) and mucositis (60%)
• One patient experienced transient Grade 1 kidney toxicity, and there were no liver toxicities observed

The adverse side effects were those that are expected of anthracycline and anthracene chemotherapeutics and were similar to or lower than those seen in the historical bisantrene trials. Importantly, no anaphylactoid-type reaction was observed in any patient over the course of treatment; this serious adverse event was regularly observed in the historical trials. Therefore, bisantrene appears to have an acceptable safety profile and demonstrated encouraging efficacy results in patients with R/R AML, particularly in those that have extramedullary disease. These data are planned to be submitted for publication. 

Update: This study was published in the European Journal of Hematology by Jonathan Canaani and colleagues. In addition to the results presented previously, the published work amended the primary outcome to a composite of complete remission and complete remission with incomplete hematologic recovery, and secondary outcomes as OS, remission duration, type, incidence and severity of adverse events (AEs), and mutational analysis. The study also included a detailed median OS of 54 days (95% confidence interval [CI], 17 days–not reached). The remainder of the results were unchanged.⁴