Clinical trial NCT02724488: 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
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Head and Neck Cancer
Melanoma
Keywords: Advanced cancer
Advanced solid tumors
Phase I clinical trial candidates
Phase II clinical trial candidates
Phase III clinical trial candidates
Head and Neck
Melanoma
Upper Aerodigestive cancer
Oral Cavity
Immune Checkpoint Inhibitors
ICIs
ctDNA
Whole Exome Sequencing
Molecular Profiling
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Princess Margaret Hospital, Canada
First posted: 2016-03-31
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: PART 1:

Patients with a histological or cytological diagnosis of advanced solid tumors who are currently on immune checkpoint inhibitors; fulfill criteria for blood sample collection; and provided written voluntary informed consent.

PART 2:

Patients with a histological or cytological diagnosis of advanced solid tumors who are candidates for a phase I, II, or III clinical trial testing immune checkpoint inhibitors or planning to have treatment with ICIs or other immunological therapy as standard of care; have at least one biopsiable lesion deemed accessible and safe to biopsy; fulfill our institution's laboratory parameters for tumor biopsy, and provided written voluntary informed consent.

Brief summary: Two part prospective study to:

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

Detailed description: 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 tumor DNA (ctDNA) in individual patients with advanced solid tumors who are currently being treated with immune checkpoint inhibitors (ICIs). Patients' archival tumors will be requested and used for whole exome sequencing (WES) of tumor 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 tumor and blood samples collected at serial time points to investigate the clonal evolution of tumors under the selection pressure of ICIs. Patients will have image-guided fresh tumor 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 tumor 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 tumor 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 tumor 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 tumor assessment and at the time of radiological disease progression. Imaging parameters for radiomic imaging analysis will be derived from patients' routine CT scans. Fresh tumor biopsies will be used for genomic profiling to study the tumors' 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 tumor, ctDNA and PBMC DNA analyses will be used to explore tumor clonal architecture and study clonal selection or tumor 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 tumor 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.

Eligibility criteria: PART 1:

Inclusion Criteria:

1. Age \> 18 years.
2. Histological or cytological proof of metastatic solid tumors.
3. Currently receiving immune checkpoint inhibitors or other immunologic therapies of interest (to be determined by study principal investigators).
4. Willingness and ability of patient to provide signed voluntary informed consent.

Exclusion Criteria:

1. Any condition that could interfere with a patient's ability to provide informed consent such as dementia or severe cognitive impairment.
2. Any contraindication to undergoing a venepuncture.

PART 2:

Inclusion Criteria:

1. Age \> 18 years.
2. Histological or cytological proof of metastatic solid tumors.
3. At least one biopsiable lesion deemed medically accessible and safe to biopsy.
4. Candidate for one or more phase I or II or III clinical trials with immune checkpoint inhibitors at the time of study enrolment. Patients receiving approved immune checkpoint inhibitors or via special access are also eligible. Patients receiving other immunologic therapies of interest may be allowed (to be determined by study principal investigators).
5. Fulfills local institution's laboratory parameters for tumor biopsy.
6. Willingness and ability of patient to provide signed voluntary informed consent.

Exclusion Criteria:

1. Any condition that could interfere with a patient's ability to provide informed consent such as dementia or severe cognitive impairment.
2. Any contraindication to undergoing a biopsy procedure.
3. Any contraindication to undergoing a venepuncture.

Primary outcomes:
measure: Part 1: The detection of new mutations from circulating tumor DNA (ctDNA) analyses or change in the frequency of mutations found in archival tumor Whole Exome Sequencing (WES) analyses.
timeFrame: 5 years
measure: Part 2: Concordance between WES analyses of serial tumor biopsies.
timeFrame: 5 years
Secondary outcomes:
measure: Part 1: Concordance between DNA analyses of archival tumor and ctDNA analyses.
timeFrame: 5 years
measure: Part 2: Concordance between WES analyses of serial tumor biopsies and ctDNA analyses of serial blood samples.
timeFrame: 5 years
measure: Part 2: Changes in radiomic signatures of tumors between commencement of immune targeted therapies and disease progression assessed from serial CT scans.
timeFrame: 5 years
measure: Part 2: Correlation between tumor radiomic signatures from serial CT scans and genomic profiles (WES and gene expression analyses of serial tumor biopsies and ctDNA samples).
timeFrame: 5 years
measure: Part 2: Changes in levels of immune cells repertoire in peripheral circulation of patients using flow cytometry and related assays.
timeFrame: 5 years
Other outcomes:
Locations:
Study officials:
affiliation: Princess Margaret Hospital, Canada
name: Lillian Siu, MD
role: PRINCIPAL_INVESTIGATOR
References: