AML - Acute Myeloid Leukemia
Conditions
Keywords
AML, Acute Myeloid Leukemia, PDX, Patient-derived xenografts
Brief summary
The goal of this observational study is to develop new ways to test new drug combinations to kill tumour cells, in patients with acute myeloid leukemia (AML). The main questions it aims to answer are: * Are there new ways to speed up discovery of better treatments for AML patients using AML cells from individual from patients in special mice that can accept human tissue? * Do these mice show treatment responses that are similar to the individual AML patient from whom cells were derived? Participants with AML who are taking standard of care treatment of venetoclax and azacitidine will be asked to donate blood and bone marrow samples for this study.
Detailed description
Treatment options for patients with acute myeloid leukemia (AML) who are unfit or refractory to intensive chemotherapy, or who have relapsed after hematopoietic stem cell transplantation, remain limited. Hypomethylating agents (HMAs) are effective in prolonging patient survival, but they are often associated with adverse events and their therapeutic effects are temporary. By elucidating the resistance mechanisms used by AML cells, we have identified drugs that selectively sensitise these tumour cells to HMAs, with minimal toxicity to healthy blood cells. Patient-derived xenografts (PDX) have emerged as a valuable tool for drug testing in cancer research. They can better replicate the primary tumour and its environment in vivo, mimicking the disease progression and treatment responses of their corresponding donor with superior fidelity and predictive potential compared to current in vitro systems. The COSMOS-Avatar study aims to establish a drug testing platform to guide precision therapies tailored to defined tumour profiles. Tumour cells obtained over two years through altruistic donation for research will be used to generate AML PDX mouse models or avatars that will be used to compare standard of care and multiple candidate therapies simultaneously. Promising drug combinations identified through the COSMOS-Avatar study will proceed to a dedicated independent Phase I clinical trial platform to accelerate drug discovery and development of AML therapies.
Interventions
None listed
Sponsors
Cancer Institute NSW
The University of New South Wales
Australian National University
Clinical Hub for Interventional Research (CHOIR)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years and above 2. Patients with suspicion of AML requiring screening procedures 3. Documented diagnosis of AML by WHO Classification and/or International Consensus Classification. * Regardless of the number and type of prior lines of therapy or eligibility for allogeneic stem cell transplantation. * All AML subtypes are eligible. * Concurrent participation in clinical trials is allowed. 4. Documented myeloblast percentage ≥20% in the bone marrow or peripheral blood within 12 weeks of C1D1 confirmed by bone marrow aspirate or peripheral blood smear. 5. Planned to commence venetoclax and azacitidine therapy. 6. Provision of written informed consent prior to any study-related assessments or procedures being carried out.
Exclusion criteria
1\. Presence of any condition that, by assessment of the Investigator, would compromise the safety of the patient if they participated, the quality of trial data, or their adherence to the study-specified procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Endpoint - Generation of ≥20 adult AML PDX models with clinically annotated samples, including treatment regimen and clinical outcome | From enrolment (i.e., C1D1 of Ven+AZA treatment) up to end of treatment or 52 weeks post C1D1 (whichever applies first) | The outcome measures are 1) establish an adult AML PDX drug testing platform; 2) determine how accurately the AML PDX model replicates the clonal architecture and cellular characteristics of the original tumour by comparing donors' samples to AML PDX samples; 3) compare efficacy of standard of care and candidate therapies by engrafting multiple immune-deficient mice with the same donor sample; and 4) biomarker discovery through correlation of treatment response and single-cell and cytokine analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Endpoint - Frequency and phenotype of leukemic cells measured by flow cytometry in AML PDX models and primary donor samples before and after VEN+AZA treatment. | From enrolment (i.e., C1D1 of Ven+AZA treatment) up to end of treatment or 52 weeks post C1D1 (whichever applies first) | A) Peripheral blood and bone marrow samples will be collected from Cohort 1 and Cohort 2 participants at baseline and relapse and will undergo molecular and cellular characterisation, these samples will be used to generate AML PDX models. B) Cells isolated from participant samples will be used to generate adult AML PDX models by reconstituting immune-deficient mice and expand the cell stock in vivo. Expanded cells will be used to reconstitute additional immune-deficient mice. C) Samples will be collected from immune-deficient mice before and after treatment to assess the efficacy of individual treatments. Participant and PDX samples will also be compared to assess the fidelity of the PDX model to their matching donor. |
Countries
Australia
Contacts
Primary ContactJohn Pimanda, Professor
Backup ContactMark Polizzotto, Professor
Outcome results
None listed