Selection Pressure and Evolution Induced by Immune Checkpoint Inhibitors and Other Immunologic Therapies

Official Title

Selection Pressure and Evolution Induced by Immune Checkpoint Inhibitors and Other Immunologic Therapies

Summary:

Two part prospective study to: 1. investigate the feasibility of performing ultra-deep sequencing of plasma derived circulating tumour DNA (ctDNA) in individual patients with advanced solid tumours who are currently being treated with immune checkpoint inhibitors (ICIs) and 2. obtain fresh tumour biopsies and serial blood samples to investigate the clonal evolution of tumours under the selection pressure of ICIs.

Trial Description

Primary Outcome:

  • Part 1: The detection of new mutations from circulating tumour DNA (ctDNA) analyses or change in the frequency of mutations found in archival tumour Whole Exome Sequencing (WES) analyses.
  • Part 2: Concordance between WES analyses of serial tumour biopsies.
Secondary Outcome:
  • Part 1: Concordance between DNA analyses of archival tumour and ctDNA analyses.
  • Part 2: Concordance between WES analyses of serial tumour biopsies and ctDNA analyses of serial blood samples.
  • Part 2: Changes in radiomic signatures of tumours between commencement of immune targeted therapies and disease progression assessed from serial CT scans.
  • Part 2: Correlation between tumour radiomic signatures from serial CT scans and genomic profiles (WES and gene expression analyses of serial tumour biopsies and ctDNA samples).
  • Part 2: Changes in levels of immune cells repertoire in peripheral circulation of patients using flow cytometry and related assays.
This feasibility study will be conducted in two parts. The first part is mainly designed to investigate the feasibility of performing ultra-deep sequencing of plasma derived circulating tumour DNA (ctDNA) in individual patients with advanced solid tumours who are currently being treated with immune checkpoint inhibitors (ICIs). Patients' archival tumours will be requested and used for whole exome sequencing (WES) of tumour DNA. Blood samples at a single time point will be collected for ctDNA analysis and germ line DNA analysis (to study normal variants) using next generation sequencing. The second part is designed as a prospective research study in which patients will have tumour and blood samples collected at serial time points to investigate the clonal evolution of tumours under the selection pressure of ICIs. Patients will have image-guided fresh tumour core needle biopsy at a maximum of 3 time points: 1. prior to commencement of ICIs, and 2. when disease response to therapy is confirmed by standard radiology RECIST 1.1 criteria and/or immune related response criteria, and 3. when radiological disease progression on therapy is confirmed by RECIST 1.1 criteria. Patients who have disease response to immunotherapy could have up to 3 fresh tumour biopsies (all 3 time points) when those who do not respond to therapy will only have one biopsy (1st time point). For patients who will have a mandatory on treatment biopsy as part of a separate clinical trial (within which they are receiving ICIs) at time points different from this study, investigators will request one extra core tumour material for research use within SPECIAL if it is feasible and safe judged by a staff radiologist. Blood samples for ctDNA analysis will be collected at commencement of treatment and every 6-12 weeks thereafter ideally coinciding with radiological tumour assessments whenever possible until radiological disease progression is confirmed using RECIST 1.1 criteria. Normal genomic DNA derived from peripheral mononuclear cells (PBMC) will be extracted from one tube of whole blood collected at baseline to study normal variants. Blood samples for studying changes in immune cells repertoire and immune related amino acids, peptides, proteins and their metabolites in peripheral circulation will be collected at baseline, 6-12 weeks after starting treatment coinciding with the 1st radiological tumour assessment and at the time of radiological disease progression. Imaging parameters for radiomic imaging analysis will be derived from patients' routine CT scans. Fresh tumour biopsies will be used for genomic profiling to study the tumours' mutation spectrum by WES and level of gene expressions. PBMC DNA will be analysed by WES to study normal variants. Mutation profiling of ctDNA will be performed using next generation DNA sequencing approaches. Genomic data derived from tumour, ctDNA and PBMC DNA analyses will be used to explore tumour clonal architecture and study clonal selection or tumour evolution under selection pressure induced by ICIs or other immunological therapies. Changes in radiomic imaging signatures during treatment with immune checkpoint inhibitors and their correlation with genomic signatures will also be examined. Using blood samples collected at baseline, at the time of 1st radiological tumour assessment and at the time of disease progression, dynamic changes in immune cells repertoire and immune related amino acids, peptides, proteins and their metabolites in the peripheral circulation of patients during treatment with ICIs will also be explored.

View this trial on ClinicalTrials.gov

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Resources

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