Clinical trial NCT04107168: Microbiome Immunotherapy Toxicity and Response Evaluation
Official title: An Observational Study to Evaluate the Microbiome as a Biomarker of Efficacy and Toxicity in Cancer Patients Receiving Immune Checkpoint Inhibitor Therapy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Melanoma
Renal Cancer
Lung Cancer
Keywords: NSCLC
Advanced
Unresectable
Microbiome
Adjuvant
Resected
Immune checkpoint inhibitors
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Microbiotica Ltd
First posted: 2019-09-27
Enrollment: 1800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Up to 1800 cancer patients due to receive anti-PD(L)1 +/- anti-CTLA-4 antibodies for treatment of their cancer and up to 360 consenting adults (household controls) who live with one of these cancer patients.

Brief summary: This is a observational study to investigate how the microbiome correlates with efficacy and toxicity of immune checkpoint inhibitors in patients with advanced cancer.

Detailed description: The gastrointestinal microbiome of a healthy individual is comprised of many hundreds of bacteria species and thousands of bacteria strains. The composition of bacteria in an individual's microbiome can change over time and this can be influenced by factors including diet, drugs, genetics and infection. These bacteria play a central role in digestion of food, development and regulation of our immune system as well as our resistance to pathogens. Recent evidence suggest that a patient's intestinal microbiota composition plays a critical, though as yet poorly defined, role in determining both therapeutic efficacy and likelihood of significant adverse events to T-cell checkpoint inhibitor immunotherapy.

Immune checkpoint inhibitors are revolutionising treatment of many types of metastatic cancer, including melanoma, renal and non-small cell lung cancer, in the expectation of improving patient overall survival. However, they have limitations as they do not work for all patients and can cause unpredictable, complex immune-related toxicities. The investigators will perform a detailed study of cancer patients receiving checkpoint inhibitors. Saliva and a series of stool samples will be collected from each patient to analyse their microbiome and will be linked to treatment response, by examining blood samples and - if available - tumour and organ samples. The investigators hope this work will enable personalisation of patient immunotherapies based on microbiome biomarkers, as well as precisely manipulate a patient's microbiota to optimise their immunotherapy.

In addition, participants who have consented to take part in an optional sub-study may be offered a single nasopharyngeal swab for COVID-19 antigen before study entry. The investigators hope that that this identify correlations between the microbiome and COVID-19.

Comparison with a limited cohort of healthy household members (up to 360 volunteers) acting as controls will provide additional essential information about the role of the patient-specific microbiome.

Eligibility criteria: Inclusion Criteria for cancer patients:

* Signed informed consent

  * Aged ≥18 years old
  * Histological or cytological confirmation of invasive malignancy
  * Due to commence palliative, adjuvant or neoadjuvant systemic therapy including an anti-PD-(L)1 antibody +/- anti-CTLA-4 antibody
  * Patients with unresectable disease must have radiologically and/or clinically measurable disease, by RECIST version 1.1; target lesions must not have been previously irradiated; baseline tumour assessments must be performed within 45 days prior to starting immune checkpoint inhibitor treatment
  * Received no prior immune checkpoint inhibitors (previous treatment with other types of anti-cancer therapy is determined by patient cohort; for patients with unresectable disease, prior adjuvant therapy with immune checkpoint inhibitor(s) is allowed).
  * Willing and able to comply with scheduled visits, treatment plans, sample collections and other study procedures

Exclusion Criteria for cancer patients:

* Other invasive malignancies diagnosed within the last year which are not fully resected, or in complete remission, or for which additional therapy is required
* Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk, or interfere with their ability to comply with the study. Examples may include, but are not limited to:

  * Patients with uncontrolled ischaemic heart or other cardiovascular event (e.g. myocardial infarction, new angina, stroke, transient ischaemic attack, or new congestive cardiac failure) within the last 6 months
  * Presence of active infection
  * Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C
  * Current active, severe, or uncontrolled autoimmune condition, including but not limited to Crohn's disease and ulcerative colitis.
* Women who are pregnant, plan to become pregnant or are lactating during the study period.
* Requirement for non-physiological dose of oral steroids, or regular use of any other immunosuppressive agents; less than 10mg prednisolone or equivalent doses are allowed. Use of inhaled or topical steroids is allowed.

Household control eligibility requirements:

Confirmation of suitability to be a household control participant will be determined by completing a self-assessed questionnaire either at home or in clinic.

Household controls must:

* NOT have had any gastrointestinal infections i.e., parasites, viruses or diarrhoeal episodes during the last 6 months.
* NOT have taken antibiotics for at least 6 months
* NOT have or be recovering from any chronic intestinal disease such as:

  * Crohn's disease
  * Ulcerative colitis
  * Coeliac disease
  * Irritable bowel syndrome
  * Stomach ulcers
* NOT have a chronic autoimmune disease or significant allergies e.g., multiple sclerosis, asthma requiring regular medication, psoriasis.
* NOT have and NOT be recovering from any form of cancer.
* NOT take proton pump inhibitors, steroids, other non-steroidal anti-inflammatory drugs such as ibuprofen or aspirin.
* NOT had requirement to be hospitalised for treatment of COVID-19

In addition, household controls must sign informed consent and be aged ≥18 years old.

Primary outcomes:
measure: Can the microbiome signature predict progression-free survival (PFS) of 1 year or greater
timeFrame: Minimum 1 year PFS
Secondary outcomes:
measure: Can the microbiome signature predict PFS
timeFrame: 1 year & 2 years PFS
measure: Can the microbiome signature overall survival (OS)
timeFrame: Up to 6 years
measure: Can the microbiome signature to predict relapse
timeFrame: 1 year & 2 years relapse-free survival (RFS)
measure: Does the microbiome correlate with treatment efficacy
timeFrame: Up to 6 years
measure: Correlate microbiome findings with incidence and characteristics of immune-related adverse events
timeFrame: Up to 6 years
measure: Correlation microbiome findings and known characteristics of patients
timeFrame: Up to 6 years
measure: Control for the microbiome of cancer patients
timeFrame: Up to 6 years
measure: Build a library of biological samples for future research
timeFrame: Up to 6 years
Other outcomes:
Locations:
city: Bath
country: United Kingdom
facility: Royal United Hospitals Bath NHS Foundation Trust
city: Bournemouth
country: United Kingdom
facility: University Hospitals Dorest NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Velindre University NHS Trust
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: King's Lynn
country: United Kingdom
facility: The Queen Elizabeth Hospital King's Lynn NHS Foundation Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Foundation Trust
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
city: Taunton
country: United Kingdom
facility: Somerset NHS Foundation Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospitals NHS Trust
Study officials:
affiliation: Cambridge University Hospital
name: Pippa Corrie
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thompson NA, Stewart GD, Welsh SJ, Doherty GJ, Robinson MJ, Neville BA, Vervier K, Harris SR, Adams DJ, Dalchau K, Bruce D, Demiris N, Lawley TD, Corrie PG. The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy. BMC Cancer. 2022 Jan 24;22(1):99. doi: 10.1186/s12885-021-09156-x.