Acute myeloid leukemia Acute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100000 people in the US and is higher in patients older than 65 years. There has been a steady improvement in survival over the decades, more noticeably so in younger patients and in the last decade. Azacitidine and Venetoclax is now the standard treatment of newly diagnosed AML ineligible for intensive chemotherapy, while still facing the dilemma of relapse and refractory disease.
Anthracycline-based chemotherapeutics were wildly used in the treatment of fit AML patients. While the cardiovascular toxicity leading to morbidity and mortality limited the use of daunorubicin/idarubicin in unfit patients. Aclarubicin, also known as aclacinomycin A, is an anthracycline type of antibiotic with significant anti-cancer properties. Previous studies have shown that aclarubicin only induces histone eviction without causing DNA damage, and it stands out in pre-clinical models and clinical studies, as it potently kills AML cells. Meanwhile, aclarubicin lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. CAG regimen, combined with low-dose cytarabine, aclarubicin and G-CSF has been widely used in China and Japan for treatment of AML.
The purpose of this study is to determine the maximum tolerated dose, safety and efficacy of aclarubicin combined with azacitidine and venetoclax for subjects with newly diagnosed and relapsed /refractory AML.
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Age 18 or above.
Phase I cohort: Adults ≥18 years with newly diagnosed AML who's not a candidate for intensive chemotherapy (criteria include age ≥75, significant cardiac/pulmonary/hepatic/renal comorbidities, CGA assessment unfit for IC, etc.) or declines.
Phase II cohort A: Adults ≥18 years with newly diagnosed AML who's not a candidate for intensive chemotherapy (criteria include age ≥75, significant cardiac/pulmonary/hepatic/renal comorbidities, CGA assessment unfit for IC, etc.) or declines.
Prior therapies
Phase I cohort: Patients with prior therapy are not eligible. Patients with a history of myeloproliferative disorders (MPNs), including primary myelofibrosis (PMF), polycythemia vera (PV), chronic myeloid leukemia (CML) excluding essential thrombocythemia (ET); or myelodysplasia-myeloproliferative neoplasms (MDS-MPNs), including chronic monocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), and acute promyelocytic leukemia (APL) are not eligible.
Phase II cohort A: Same as for Phase I cohort.
Phase II cohort B: Patients relapsed/refractory to prior lower intensity therapy for AML are not eligible. No restriction on number of prior therapies.
Single group
Aclarubicin
DrugInduction (Cycle1) Phase I starting dose 20mg/m\^2 D1-D2 (dose group 1), 20mg/m2 D1-D3 (dose group 2), 20mg/m2 D1-D4 (dose group 3), ivgtt, Qd The Phase II dose was determined based on the Phase I results Consolidation (Cycle 2-6) Phase I starting dose 20mg/m\^2 D1-D2 (dose group 1), 20mg/m2 D1-D3 (dose group 2), 20mg/m2 D1-D4 (dose group 3), ivgtt, Qd The Phase II dose was determined based on the Phase I results
Venetoclax
DrugCycle 1 (Induction) 100mg on day 1, 200mg on day 2, 400mg on days 3-14 Cycles 2-6 (Consolidation) 400 mg orally daily on days 1-7
Azacitidine
DrugCycle 1 (Induction) 75 mg/m\^2 SC on days 1-7 of each cycle Cycles 2-6 (Consolidation) 75 mg/m\^2 SC on days 1-7 of each cycle Cycles 7-18 (Maintenance) 50 mg/m\^2 SC on days 1-5 of each cycle
Maximum tolerated dose (MTD)
MTD for aclarubicin (primary outcome measure of phase I)
Recommended Phase 2 Dose (RP2D)
RP2D for aclarubicin (primary outcome measure of phase I)
Event-free survival (EFS)
primary outcome measure of phase II, cohort A
Composite Complete Remission (CCR)
primary outcome measure of phase II, cohort B
Composite Complete Remission (CCR)
Preliminary efficacy assessment (secondary outcome measure of phase I). Proportion of patients who achieved CR+CRi+CRh.
Complete Remission Rate (CRR)
Preliminary efficacy assessment (secondary outcome measure of phase I). Proportion of patients who achieved CR.
Adverse Events
Number of participants with treatment-related adverse events as assessed by CTCAE v6.0
Association between baseline genomic alterations and composite complete remission (CCR)
Baseline genomic alterations will be assessed using next-generation sequencing. Composite Complete Remission (CCR) will be evaluated according to standard response criteria, and associations with genomic alterations will be analyzed.
Change in quality of life as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status score
Quality of life will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The global health status score ranges from 0 to 100, with higher scores indicating better quality of life. Scores will be calculated according to the EORTC scoring manual and summarized as change from baseline.
Cancer-related fatigue as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue score
Cancer-related fatigue will be assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Scores are reported as T-scores standardized to a reference population, with higher scores indicating greater fatigue (worse outcome). Changes from baseline will be summarized.
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Shanghai Jiao Tong University School of Medicine
Lead sponsor
Leiden University Medical Center
Collaborator
Fred Hutchinson Cancer Center
Collaborator
Washington University School of Medicine
Collaborator
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