Clinical trial NCT06782971: Evaluation of Combined Sensitising and Hypomethylating Therapy Outcomes in AML PDX
Official title: COSMOS-Avatar: Evaluation of Combined Sensitising and Hypomethylating Therapy Outcomes in AML PDX
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: AML - Acute Myeloid Leukemia
Keywords: AML
Acute Myeloid Leukemia
PDX
Patient-derived xenografts
Lead sponsor: Clinical Hub for Interventional Research (CHOIR)
Sponsor class: OTHER_GOV
Collaborators: name: Cancer Institute NSW
name: The University of New South Wales
name: Australian National University
First posted: 2025-01-20
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study population is people who have recently been diagnosed with or are suspected of having AML and undergoing investigational procedures, and whose doctor plans to start them on venetoclax and azacitidine. Around 25 people from different hospitals in Australia will take part in this project.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Primary Endpoint - Generation of ≥20 adult AML PDX models with clinically annotated samples, including treatment regimen and clinical outcome
timeFrame: From enrolment (i.e., C1D1 of Ven+AZA treatment) up to end of treatment or 52 weeks post C1D1 (whichever applies first)
Secondary outcomes:
measure: 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.
timeFrame: From enrolment (i.e., C1D1 of Ven+AZA treatment) up to end of treatment or 52 weeks post C1D1 (whichever applies first)
Other outcomes:
Locations:
city: Canberra
country: Australia
facility: Canberra Health Services
state: Australian Capital Territory
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
Study officials:
affiliation: University of New South Wales
name: John Pimanda, Professor
role: PRINCIPAL_INVESTIGATOR
References: