First Patient Dosed in Phase 1b/2 AML Trial at Chaim Sheba Medical Center Israel

09 August 2021 – Race Oncology Limited (“Race”) is pleased to announce that the first patient has been dosed in the Phase 1b/2 trial in relapsed/refractory Acute Myeloid Leukaemia (ASX Announcement: 22 June 2021).

This investigator-led trial supervised by Professor Arnon Nagler will use Zantrene® (bisantrene dihydrochloride) in a novel three drug combination which has demonstrated compelling efficacy in pre-clinical studies (ASX Announcement: 10 May 2021). Prof Nagler was the Principal Investigator of the Phase 2 investigator-initiated trial where Zantrene was used as a single agent in R/R AML patients and reported an impressive 40% clinical response rate (ASX Announcement: 16 June 2020).

“We are delighted to see the start of this important clinical project which uses a novel combination approach for relapsed or refractory Acute Myeloid Leukaemia. This study is also an important step in our journey towards approval of Zantrene® in this area of high unmet medical need.”

Race CMO Dr David Fuller

The trial will run in parallel with a separate Australian Phase 2 trial in patients with extramedullary AML (ASX Announcement: 2 June 2021).

Both trials are key components of Race’s Three Pillar strategy.

Even when CR is achieved through intense chemotherapy, approximately half of the younger and 80% of the older patients, relapse. In both clinical situations, refractory and/or relapsed AML, active disease remains a major therapeutic challenge despite recent advances in the clinic.

“This study led by Professor Nagler who has good experience with Zantrene®, supports the building of additional data in AML in line with our Three pillar strategy plan. We hope to see improved patient outcomes in what has been historically a difficult to treat disease. We plan on using our trademarked name, Zantrene®, in referring to bisantrene dihydrochloride. It’s one of our registered trademarks and its protection is enhanced by its ongoing and appropriate use.”

Race CEO & MD Phillip Lynch

Relapsed or Refractory Acute Myeloid Leukemia

Primary refractory or relapsed Acute Myeloid Leukemia is associated with poor prognosis and remains a serious therapeutic challenge. Primary refractory AML is defined by the absence of complete remission (CR), manifested by blast count of ≥5% in bone marrow after one or two cycles of intense induction chemotherapy.

Up to 30% of adults with newly diagnosed AML fail to achieve CR after two courses of intensive chemotherapy.

Clinical Trial Design

The trial is an open-label, Phase 1b/2 study of intravenous FluCloZan (Fludarabine, Clofarabine, Zantrene®) in cohorts of up to 12 adult patients with R/R AML with a Phase 1b dose escalation stage to establish the maximum tolerated dose (MTD) or recommended Phase 2 dose  of the combined FluCloZan regimen, followed by a Phase 2 expansion stage to determine efficacy and confirm safety of FluCloZan at the recommended Phase 2 dose in up to 17 patients.

Phase 1b, Dose-Escalation (Lead-in Stage)

A two-cohort dose escalation schema using a standard 3 + 3 design will be employed.

Cohort 1 will enroll three patients to receive the FluCloZan regimen for four consecutive days. If no dose limiting toxicities (DLTs) have occurred in the first three patients by day 30 of their first cycle of treatment, then Cohort 2 will receive the treatment for five days (with the extra day representing dose escalation).

Phase 2, Expansion (Efficacy Stage)

Up to 17 patients will be enrolled into a Phase 2 expansion efficacy cohort using a 2-stage Simon design. Initially, 9 patients will be enrolled and treated with the recommended Phase 2 dose of FluCloZan as determined in the Phase 1b part of the study. If there are no patient responses in the first nine subjects according to the response criteria outlined in the European Leukemia Net (ELN) guidelines, the study will be terminated for futility. If at least one patient shows a response, eight more patients will be enrolled and treated. If three or more of the patients treated in Stage 2 respond, the null hypothesis of treatment futility can be rejected.

Efficacy assessments will be based on bone marrow examination at a minimum of two time points on Day 21 and on Day 30. A further bone marrow examination may be performed on Day 42 at the investigator’s discretion, based on patient’s disease and performance status and/or on peripheral blood hematology results during the treatment course and between Day 21 to 42.

Treatment will be terminated upon any sign of progressive/recurrent disease and/or referral to pre-transplant conditioning therapy for (allogeneic) stem cell transplantation.

Patients who do not progress or experience any DLTs may receive a second course of treatment for the same duration as in their first cycle.

All patients will be actively followed-up every three months for a further 12 months following completion treatment for disease free survival (DFS) and overall survival (OS).

Indicative Costs and Timelines

The trial is expected to take 36 to 40 months to complete with full patient recruitment over approximately 18 months.  Given the trial is open-label, Race expects that data will be reported at interim points throughout the trial.

Race will pay Chaim Sheba a total fee of USD $668,739 over the study’s life. Payments will be made to Chaim Sheba upon reaching key milestones and the total trial cost will depend on the number of patients recruited and other operational variables.

Clinical Trial Summary

Study TitleAn Open-label, Phase Ib/II, Two-stage, Study of Zantrene® (Bisantrene) in combination with Fludarabine and Clofarabine as Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukaemia (AML)
Phase of DevelopmentPhase 1b/2
Active IngredientBisantrene dihydrochloride, Fludarabine, Clofarabine (FluCloZan)
Study DescriptionPhase 1b/2 study of FluCloZan, IV, in cohorts of adult patients with R/R AML using a 2-stage design: a Phase 1b lead-in dose escalation stage to establish the MTD or RP2D of FluCloZan and a Phase 2 expansion stage to determine efficacy and confirm safety of the FluCloZan regimen at the RP2D.
Principal InvestigatorProfessor Arnon Nagler
SponsorRace Oncology
Indication/populationAdult men and women 18 to 65 years of age with relapsed and/ or refractory Acute Myeloid Leukemia (R/R AML) presenting with non-CNS extramedullary disease.
Number of SubjectsPhase 1b: up to 12 patients Phase 2: up to 17 patients in the expansion phase
Study Period36 – 40 months
Study DesignA two-cohort dose escalation schema using a standard 3 + 3 design will be employed followed by an expansion phase at the RP2D. As the patient population is considered relapsed and/or refractory to existing treatments, a comparator arm will not be used.
Statistical methodsSimon 2 stage design
End PointsPrimary
Phase 1b Dose Escalation: number of subjects experiencing a DLT in each cohort Phase 2 Expansion: Overall Response Rate (ORR) defined as the proportion of subjects with CR and CRi between Day 30 to Day 42 Secondary: Transplant/allo-HSCT rates (for transplant/allo-HSCT-eligible subjects); Combined CR and CRi and PR response rate; Morphologic leukemia-free state (MLFS); Partial remission (PR); Stable disease (SD); Progressive disease (PD); Relapse; Disease free survival (DFS); Overall survival (OS); Time to next treatment (for transplant/allo-HSCT-ineligible subjects)
Participating Centres 1 Chaim Sheba Medical Center, Tel Hashomer, Israel
DatesFirst patient August 6, 2021; Last patient (anticipated): Q3 CY2023