New study design with well-known drug for CHDR’s first integrative oncology study

'Imatinib was the big breakthrough in oncology at the beginning of this century,' says Dr Jacobus (Co) Bosch, Research Director Oncology. 'It was the first molecular targeted drug that made a huge impact in changing the treatment paradigm of chronic myeloid leukaemia (CML). Subsequent successful application in gastro-intestinal stromal tumours (GIST) and other diseases set the stage for new oncologic treatment regimens beyond classical chemotherapy. We chose this well-known compound to safely explore our novel early oncology drug development concept, building a bridge between studies in healthy volunteers and patients.'

CHDR’s Oncology group decided to study imatinib in healthy volunteers because of its favourable safety profile in healthy volunteers, its well-known mechanism of action with relevant biomarkers and its use in the treatment of a variety of malignant and non-malignant diseases. Bosch and his colleagues plan to contribute to the understanding of imatinib’s pharmacodynamics by studying how imatinib targets the c-kit receptor in bone marrow cells and in blood cells. In a method development study successfully completed in the summer of 2023, the Oncology group has already developed a procedure for bone marrow aspiration and analysis.

Bosch: 'We want to map the inhibition of c-kit and its downstream tyrosine-kinase signalling pathway as precisely as possible in healthy volunteers and in cancer patients. We have set up an advanced phospho-flowcytometric measurement method in the Immunology laboratory to do that in fresh cells from the blood and bone marrow compartments.’

Integrating healthy volunteers in early oncology trials has valuable advantages for drug development programmes. Bosch: 'Healthy volunteers allow for a comprehensive evaluation of the pharmacological effect and optimal dose-finding of oncology drugs because they have no comorbidity and do not use medication.’ Early pharmacodynamic biomarker measurement is a key component of this approach, as it provides a pharmacodynamic dataset that can be used to plan the first studies in patients. Bosch emphasises that before the first-in-human studies, the risks for study participants must be thoroughly evaluated using CHDR’s IB-Derisk analyser. It may not be feasible to test some compounds in healthy volunteers.

‘CHDR’s oncology concept is aligned with new regulatory developments such as FDA’s Project Optimus. It has the potential to accelerate study timelines for an expedited start in cancer patients.

For cancer patients in an early phase clinical trial, starting with a dose which is safe, tolerable and effective may have great advantages,’ says Bosch.

The imatinib study aims to lay the foundation for this integrative approach to oncology studies. CHDR’s new hospital-integrated clinical research unit is another important element. The imatinib study protocol was developed in close interdisciplinary collaboration with various external partners, including clinical oncologists, biostatisticians, clinical pharmacologists, regulatory agencies and stakeholders from academia and industry.  Bosch: ‘Building on CHDR’s strong clinical pharmacology basis, we are enjoying increasing traction, breaking new ground and continuing to successfully position CHDR in clinical oncology. Our goal is to contribute to developing better oncology drugs and improving the survival of cancer patients.’