Microbiome Immunotherapy Toxicity and Response Evaluation

CCTU- Cancer Theme

Status: Enrolling

Conditions: Melanoma; Renal Cancer; Lung Cancer

Treatments: Drug: Atezolizumab; Drug: Ipilimumab; Drug: Tremelimumab; Drug: Bevacizumab; Drug: Pembrolizumab; Drug: Nivolumab; Drug: Durvalumab

Study type: Observational

Funder types: Other; Industry

Identifiers

NCT04107168

C7535/A27717 (Other Grant/Funding Number)

MITRE

Details and patient eligibility

About

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

Full 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.

Enrollment: 1,800 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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.

Trial design

1,800 participants in 9 patient groups

Cohort 1

Description:

Disease: Unresectable AJCC (American Joint Committee on Cancer) stage 3 or 4 melanoma. Anti-PD-1 monotherapy (Nivolumab or Pembrolizumab). Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Drug: Pembrolizumab

Cohort 2

Description:

Disease: Unresectable AJCC stage 3 or 4 melanoma. Nivolumab + Ipilimumab. Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Drug: Ipilimumab

Cohort 3

Description:

Disease: Advanced renal cell carcinoma. Anti-PD-(L)1 + kinase inhibitor. Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Cohort 4

Description:

Disease: Advanced renal cell carcinoma Nivolumab + Ipilimumab. Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Drug: Ipilimumab

Cohort 5

Description:

Disease: Advanced NSCLC Anti-PD-(L)1 (Nivolumab, Pembrolizumab or Atezolizumab) monotherapy in the first line setting. Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Drug: Pembrolizumab

Drug: Atezolizumab

Cohort 6

Description:

Disease: Advanced NSCLC Anti-PD-(L)1 (Nivolumab, Pembrolizumab or Atezolizumab) + chemotherapy +/- antiangiogenic (Bevacizumab) in the first line setting. Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Drug: Pembrolizumab

Drug: Bevacizumab

Drug: Atezolizumab

Cohort 7

Description:

Disease: Resected AJCC stage 3 or 4 melanoma. Anti-PD-1 monotherapy (Nivolumab or Pembrolizumab). Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Nivolumab

Drug: Pembrolizumab

Cohort 8

Description:

Disease: Resected renal cancer Anti-PD-(L)1 monotherapy (Durvalumab or Pembrolizumab). Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Durvalumab

Drug: Pembrolizumab

Cohort 9

Description:

Disease: Resected renal cancer Durvalumab + Tremelimumab. Dosage form, dosage, frequency and duration will be either standard of care and accessed via normal commissioning arrangements, or will be part of an ethics-approved clinical trial, where co-enrollment into an observational study is permitted.

Treatment:

Drug: Durvalumab

Drug: Tremelimumab