Clinical Trials of an Investigational MDM2-TP53 Antagonist
Research type
Research Study
Full title
Research protocol for the development and analytical validation of diagnostic assays to determine enrolment onto 1a and 1b Clinical Trials of an Investigational MDM2-TP53 Antagonist
IRAS ID
241044
Contact name
Richard Kennedy
Contact email
Sponsor organisation
Almac Diagnostics Ltd
Duration of Study in the UK
4 years, 0 months, 1 days
Research summary
Summary of Research
The objectives of this research study is to develop and analytically validate a Next Generation Sequencing (NGS) assay and a Fluorescent in situ hybridisation (FISH) assay as clinical trial assays (CTAs) to be used to detect clinically relevant aberrations of the TP53 gene in patients with advanced TP53 wild-type enriched solid tumors initially for retrospective testing in a Phase Ia dose escalation clinical trial and then to be used prospectively to determine a patient’s molecular eligibility for enrolment onto a Phase Ib clinical trial dose expansion study to determine the recommended dose of a MDM2-TP53 antagonist for further development in patients with selected advanced or metastatic solid tumors.
Summary of Results
This study tested formalin-fixed paraffin embedded (FFPE) tumor tissue using in vitro diagnostic devices- the Almac TP53 CTA v3 ADX17083, and the MDM2/CEP12 FISH CTA. The testing was performed to retrospectively confirm results for patients deemed eligible for a pharmaceutical company's clinical trial (1403-0001) who had previously had a result generated by a local test, and to prospectively test patients for their eligibility onto the 1403-0001 clinical trial based on their TP53/MDM2 gene status where no local test result was available. The 1403-0001 clinical trial is investigating a drug for the treatment of patients with non-small cell lung cancer (NSCLC), bladder cancer, glioblastoma, sarcoma and solid tumours with brain metastases. Most patients with advanced or metastatic tumours have poor outcomes, highlighting the need for new treatments. TP53 is a crucial tumor suppressor gene, often mutated in about 50% of cancers. In cancers with wild-type (non-mutated) TP53, its function can be inhibited by overexpression of MDM2. MDM2-p53 antagonists can reactivate TP53 in these cases. The investigational drug in the 1403-0001 clinical trial is a MDM2-p53 antagonist that inhibits the interaction between the tumor suppressor TP53 and its negative regulator MDM2. Due to the mechanism of action of this drug, to be eligible for enrolment onto the 1403-0001 trial, patients must have a documented TP53 wild-type and MDM2-amplified solid tumors. Almac Diagnostic Services performed exploratory molecular analysis on 54 samples for the Phase 1a portion of the 1403-0001 trial. Almac Diagnostic Services performed molecular analysis of samples and provided 153 Subject Test Reports for the Phase 1b portion of the trial.
REC name
East of England - Cambridgeshire and Hertfordshire Research Ethics Committee
REC reference
18/EE/0311
Date of REC Opinion
20 Sep 2018
REC opinion
Favourable Opinion