- Bisantrene in combination with fludarabine and clofarabine administered over four days induced a clinical response in 6 of 15evaluable patients (40%) with advanced relapsed or refractory Acute Myeloid Leukaemia, with five patients receiving apotentially curative stem cell transplant
- The bisantrene combination was found to be safe and well tolerated without clinically relevant cardiotoxicity or tumour lysissyndrome
- The trial abstract has been peer-reviewed and the interim results selected for presentation at the prestigious American Society of Hematology 65th Annual Conference, 9-12 December 2023.
6 November 2023 – Race Oncology Limited ("Race") is pleased to announce interim clinical results from an ongoing investigator-initiated Phase 2 trial of bisantrene in combination with fludarabine and clofarabine in relapsed or refractory Acute Myeloid Leukaemia (R/R AML) patients. The trial is running at the Sheba Medical Centre, Israel, under the supervision of key opinion leader Professor Arnon Nagler. Results of this trial have been chosen by the conference committee for presentation at the prestigious American Society of Hematology (ASH) 65th Annual Conference being held on the 9-12 December 2023.
The oral poster presentation entitled "Bisantrene in combination with Fludarabine and Clofarabine as Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) – An Open- label, Phase II Study" describes clinical results from the first 15 evaluable patients treated on study since August 2021 (NCT04989335). The presentation abstract was released from embargo by ASH on 2 November 2023.1
Highly Positive Interim Results
Six of the 15 evaluable patients (40%) responded to Bis/Clo/Flu treatment (five complete responses, one partial response), with three of the clinical responders having active extramedullary disease (EMD). Five of the six treatment-responsive patients were able to be bridged to a stem cell transplant (SCT) within one to three months of treatment. Of the five stem cell transplanted patients, three have since died; one from graft-versus-host disease, one who relapsed within four months oftransplant, and one of infection after two years. The two other patients remain disease free and in complete remission.
Professor Dr Anoop Enjeti, Director of Haematology at the Calvary Mater Newcastle and John Hunter Hospitals commented: "This clinical trial of bisantrene in combination with intensive chemotherapy produced very encouraging results in younger AMLpatients with advanced relapsed, refractory and resistant acute myeloid leukaemia (AML). Many of these patients achieved a complete or a partial remission, enabling a significant proportion to go on to a bone marrow transplant. These impressive results provide proof of concept supporting further trials of bisantrene in combination with other AML treatments to improve outcomes for this leukaemia."
Prof. Enjeti is an independent specialist in haematological cancers including AML and was not involved with the Sheba study. He is a highly experienced clinical haematologist, having designed and led more than 25 clinical trials and is the co-chair of the MDS/AML working party for the Australasian Lymphoma and Leukemia Group (ALLG) for Cooperative Clinical Trials.
Executive Director, Dr Pete Smith commented: "These are highly positive outcomes in a heavily pre- treated patient population. We await with interest the release of the poster at ASH in December. To see such meaningful clinical responses in a group that would typically be receiving palliative care is striking. It is also encouraging that the safety profile was manageable, even for this advanced patient population."
Patient Population
The median patient age was 48 years (range 19-69) and the median number of prior lines of therapy was four (range 3-9). All patients were refractory to prior regimens, which included cytarabine/daunorubicin; fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-Ida), venetoclax; azacitidine; gilteritinib, radiation therapy, and CAR-CD19 for 8:21 (genotype) AML.
Due to the expected low probability of achieving a clinical response in this treatment resistant patient population, the primary endpoint for the study was 'any clinical response' (partial response, complete response, or complete response with incomplete blood count recovery). The secondary endpoint was 'any clinical response that enabled a stem cell transplant'. Safety and cardiac monitoring data were captured as exploratory endpoints.
Five patients died from disease progression or bacterial/fungal infection before they could be evaluated for a clinical response to treatment. This was not an unexpected outcome given the advanced disease state of this heavily pre-treated salvage AML patient population. A recent retrospective analysis at the MD Anderson Cancer Center of 1258 salvage AML patients who had received a median of less than two lines of salvage treatment, found the early mortality rate to be almost one in five patients (18%) during salvage therapy.2
Treatment side-effects
The most common side-effect was treatment-related neutropenic fever, observed in 18 patients. Ten patients developed transient liver toxicity (Grade 1-3) that resolved in all patients with conservative therapy. Transient liver toxicity is a well-known toxicity of clofarabine, where rates of up to 60% have been observed in multiple clofarabine-containing treatment regimens.3,4 Four patients had Grade I (mild) renal toxicity and seven had mild fluid retention.
Importantly, clinically relevant cardiotoxicity was not observed in any patients. Clofarabine has been associated with rates of heart left ventricular systolic dysfunction of up to 27% in clofarabine-containing treatment regimens.5
Conclusion
Professor Nagler, the study Principal Investigator, concludes in the abstract: "These rather impressive results in such a heavily pre-treated population support further studies of bisantrene-based combinations, including those with venetoclax or hypomethylating agents."1
About us:
Race Oncology (ASX: RAC) is an ASX-listed clinical stage, global biotechnology company with a dedicated mission to be atthe heart of cancer care.
Race's lead asset, bisantrene, is a small molecule anthracene chemotherapeutic. Bisantrene has a unique and rich clinical history with demonstrated therapeutic benefits in both adult and paediatric patients, a well characterised safety profile, andcompelling clinical data demonstrating an anti-cancer effect and less cardiotoxicity than other comparable agents.
Race is developing bisantrene to address the high unmet need of patients across multiple oncology indications, with an initialfocus on metastatic breast cancer (lead indication) and acute myeloid leukaemia (AML) exploring anti-cancer plus cardio-protection in synergy with known standards of care.
As part of its clinical and preclinical programs, Race is investigating the effect of bisantrene on the m6A RNA pathway, followingindependent research by the City of Hope identifying bisantrene as a potent inhibitor of FTO (Fat mass and obesity-associated protein). Dysregulation of the m6A RNA pathway has been described in numerous peer reviewed studies to be a driver of a diverse range of cancers.
Race Oncology is in collaboration with City of Hope, MD Anderson, Sheba City of Health and UNC School of Medicine, and isactively exploring partnerships, licence agreements or a commercial merger and acquisition to accelerate access to bisantrene forpatients with cancer across the world.
