On June 2, 2021 Race Oncology Limited ("Race") reported it has appointed the Contract Research Organisation (CRO), Parexel International, to support an open label Phase 1/2 clinical trial in patients with relapsed or refractory (r/r) extramedullary Acute Myeloid Leukemia (AML) (Press release, Race Oncology, JUN 2, 2021, View Source [SID1234583390]).

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The trial will be led by Principal Investigator Associate Professor Anoop Enjeti, Director of Haematology at the Calvary Mater Newcastle and John Hunter Hospitals.

Dr Enjeti is a highly experienced clinical haematologist having designed and led more than 25 clinical trials. Dr Enjeti is the co-chair of the MDS/AML working party for the Australasian Lymphoma and Leukemia Group (ALLG) for Cooperative Clinical Trials.

Extramedullary AML
Extramedullary AML occurs when leukaemia spreads from the bone marrow and forms solid tumours in tissues such as the skin, breast, kidney, brain, or other organs. A 2020 prospective positron imaging trial identified that up to 22% of AML patients have the extramedullary form1. Extramedullary AML patients have no clinically approved treatments and limited experimental treatment options, with many clinical trials explicitly excluding this difficult to treat form of AML.

A recent Phase 2 clinical trial in r/r AML patients treated with Bisantrene by a team led by Prof Arnon Nagler of the Chiam Sheba Medical Center, Israel reported a 100% clinical response rate (4/4 patients) in those patients with the extramedullary form of this deadly cancer (ASX announcement: 16 June 2020).

Clinical Trial Design
This open label Phase 1/2 trial will recruit approximately 60 patients with 18F-FDG PET/CT imaging-identified extramedullary AML at 10 clinical sites across Australia using a two-stratum (arm) design. The first stratum will utilise Bisantrene as a high dose, single agent, treatment over 7 days in patients with extramedullary AML who are able to tolerate high intensity chemotherapy, followed by one or more cycles of consolidation treatment of Bisantrene in combination with azacitidine, a standard of care drug.

The second stratum will use Bisantrene as a low dose FTO-targeted agent in combination with the oral hypomethylating agent, Inqovi (decitabine and cedazuridine) for patients unable to tolerate high intensity chemotherapy. Published preclinical data from the City of Hope Hospital by Prof Chen’s team identified that Bisantrene is able to synergize with decitabine2. In mouse models of AML the combination provided improved therapeutic efficacy with, lower toxicity compared to when either drug was used alone3.

The primary endpoint for both strata will be complete response (CR) and complete response with incomplete haematological recovery (CRi) with an aim of bridging to an allogeneic hematopoietic stem cell transplant. Key secondary endpoints include safety and tolerability of Bisantrene, overall and event-free survival, and the level of FTO expression with response to treatment.

Indicative Costs and Timelines
The trial is expected to take 36 to 40 months to complete with full patient recruitment over approximately 18 months. Treatment of the first patient is targeted for Q4 CY 2021, subject to human ethics approval of the study and patient recruitment.

Race will pay Parexel an initial fee of $1.11 million under the Start Up Agreement (SUA). Additional payments will be made to Parexel under the Master Service Agreement (MSA) throughout the study upon reaching key milestones and will depend on the number of patients recruited and other operational variables.

Due to the adaptive nature of this study, the total study costs cannot be determined at this stage.

Race CSO Daniel Tillett said: "We are excited to begin this study with the twin aims of exploring the use of Bisantrene to treat FTO overexpressing cancers and bring it to market as a heart safer orphan drug treatment for AML. This trial will be transformational for Race and our shareholders."

Race CEO & MD Phillip Lynch said: "This study supports our Pillar 3 registration ambition to see Bisantrene’s historical safety and efficacy in AML demonstrated with superior drug combinations that may benefit patients who remain challenged by initial treatment failures."

Clinical Trial Summary
Study Title An open label Phase 1/2 study of high dose Bisantrene with cytarabine arabinoside (Ara-C) or low dose Bisantrene with oral decitabine for treatment of relapsed or refractory Acute Myeloid Leukemia (r/r AML) patients with extramedullary disease (BISECT)
Phase of Development Phase 1/2
Active Ingredient Bisantrene dihydrochloride
Study Description A two stratum trial of Bisantrene in patients with extramedullary AML diagnosed by 18F-FDG PET/CT imaging.
Principal Investigator A/Prof Anoop Enjeti
Sponsor Race Oncology
Indication/population Adult men and women ≥18 years of age with relapsed and/ or refractory Acute Myeloid Leukemia (R/R AML) presenting with non-CNS extramedullary disease.
Number of Subjects Stratum 1: up to 30 patients Stratum 2: 4 -10 patients (dose escalation); up to 30 patients in the expansion phase
Study Period 36 – 40 months
Study Design This is a two strata Phase 2, open-label study of high dose Bisantrene treatment given as a monotherapy induction and in combination with Ara-C as consolidation (Stratum 1) and lower dose Bisantrene in combination with decitabine (Inqovi) (Stratum 2) in patients with extramedullary r/r AML. As the patient population is considered relapsed and/or refractory to existing treatments, a comparator arm will not be used.
Statistical methods Bayesian Optimal Interval (BOIN) model-based design based on observed response rate of 30% for RR AML where the true response rate is expected to be <20% applying a 90% power.
End Points Primary: Achievement of a morphological overall response, i.e. complete response (CR) or complete response with incomplete count recovery (CRi), after commencing cycle 1 and before commencement of cycle 2. Key Secondary: Achievement of a PET/radiologic overall response, i.e. complete or partial metabolic response, after cycles 1, 2 and 4. Other Secondary: FTO status, event free survival, overall survival
Participating Centres 10 ALLG participating sites across Australia
Start Date First patient In: Q4 CY2021
End Date Last Patient In (anticipated): Q2 CY2023
End Date Last Patient In (anticipated): Q2 CY2023