Prospective Analysis of Intestinal Microbiome and Autoimmune Panels as Predictors of Toxicity in ImmunOncology Patients (INSPECT-IO)

This is a single-center, investigator-initiated, non-interventional study evaluating the role of the intestinal microbiome and autoimmune panels as a predictor for developing ≥ Grade 2 CTCAE v5.0 immune-related adverse event (irAE) and/or requiring systemic immunosuppression for irAEs in advanced solid tumor patients receiving immunooncology (IO) combinations at the Princess Margaret Cancer Centre. This is a minimal risk study involving the analysis of patient samples and does not involve therapeutic intervention.

The study will involve a prospective cohort of up to 120 patients and it is anticipated that patient accrual will be completed within 18 months.

Patients will receive IO combination as per their specific protocols from their other clinical trial or per their standard of care and samples will be collected at multiple time-points. No additional visits to the hospital will be needed for this study as safety assessments are already captured for all patients based on their participation in a clinical trial or per their standard of care.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor

Detailed Description

Accumulating evidence supports that differential composition of fecal microbiome influences response to immunotherapy and development of colitis. Microbiome with different profiles are also associated with multiple diseases, including gastrointestinal (GI) or non-GI auto-immune pathologies. Little is known about the relationship between the microbiome composition or fecal calprotectin (fCal) and the development of non-colitis immune-related adverse events (irAEs) during treatment with IO combinations.

Autoimmune conditions and irAEs from immune checkpoint inhibitors (ICI) drugs both involve loss of tolerance to endogenous antigens and produce similar clinical presentations. ICI can increase humoral response. However, to date there is no evidence that autoimmune panels are correlated with the development of irAEs during IO combination therapy.

These findings suggest that analyzing the microbiome and autoimmune panels of patients treated with IO combinations at multiple time-points may be feasible. In addition, baseline, early shift and changes in microbiome and autoimmune panels at time of a serious irAE may be correlated with the development of serious irAEs and may change with appropriate immunosuppressive regimens.

We hypothesize that analysing the microbiome and autoimmune panels of patients treated with immunooncology (IO) combinations at multiple time-points is feasible. Additionally, we hypothesize that baseline, early shift and changes in microbiome and autoimmune panels at time of a serious immune-related adverse event (irAE) is correlated with the development of serious irAEs and will change with appropriate immunosuppressive regimens.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Anna Spreafico, MD; Phone Number: 3308 416-946-4501; Email: tip@uhn.ca
• Study Contact Backup: Name: Aileen Trang; Phone Number: 7754 416-946-4501; Email: aileen.trang@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • Princess Margaret Cancer Centre
      • Contact: Anna Spreafico, MD; Phone Number: 3308 416-946-4501; Email: tip@uhn.ca
      • Contact: Aileen Trang; Phone Number: 7754 416-946-4501; Email: aileen.trang@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Advanced solid tumor patients receiving immunooncology combinations

Description

Inclusion Criteria:

1. Signed written and voluntary informed consent.
2. Patient must be willing and able to provide collection for blood and stool specimen analysis at the pre-specified time-points.
3. Age > 18 years, male or female.
4. Patient must be diagnosed with any advanced solid tumor deemed incurable and to be treated at Princess Margaret Cancer Centre.
5. Patients must be eligible to treatment with an IO combination.

Exclusion Criteria:

1. Any conditions that in the opinion of the Investigator would interfere with patient safety, or evaluation of the collected specimen and interpretation of study result.
2. History of autoimmune disease with a flare episode within one year before study screening.

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of evaluating intestinal microbiome composition and autoimmune panels in patients treated with immunooncology combinations through the analysis of stool and blood samples at multiple time-points.	To assess the feasibility, the endpoint will be deemed feasible if >50% of patients have biospecimens collected in at least 2 time-points.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between baseline intestinal microbiome composition to the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	Correlation between bacteria taxa obtained through 16S rRNA sequencing and irAEs.	18 months
Correlation between baseline autoimmune panels to the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	Correlation between auto-antibodies detected through the 162 IgM and IgG antigen microarray with the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	18 month
Correlation between baseline fecal calprotectin levels to the development of ≥ Grade 2 CTCAE v5.0 colitis and/or requiring systemic immunosuppression for colitis.	Correlation between fCal detection at baseline to development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	18 months
Correlation between the early changes in composition of intestinal microbiome and the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	Correlate changes in bacteria taxa composition through 16S rRNA sequencing from baseline samples to early time-point, with the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs	18 months
Correlation between the early changes in composition of autoimmune panels and the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	Correlate the changes of auto-immune antibodies reactivity obtained through the 162 IgM and IgG antigen microarray from baseline to early time-point with the development of ≥ Grade 2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs.	18 months
Correlation between the early changes in fecal calprotectin levels to the development of ≥ Grade 2 CTCAE v5.0 colitis and/or requiring systemic immunosuppression for colitis.	Correlate the changes in fCal positivity from baseline to early time-point with the development of ≥ Grade 2 CTCAE v5.0 colitis and/or requiring systemic immunosuppression for colitis.	18 months
Evaluate intestinal microbiome, autoimmune panel reactivity & fCal changes from baseline to development of ≥ Gr2 CTCAE v5.0 irAEs and/or requiring systemic immunosuppression for irAEs, & from event diagnosis to resolution to ≤ Gr1 CTCAE v5.0 irAEs	Monitor changes in bacteria taxa through 16S rRNA sequencing; reactivity of autoimmune antibodies through 162 IgM and IgG antigen microarray; and positivity of fCal at baseline, early time-point, at the time of event diagnosis, and at the time of event resolution	18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the overall response rate (ORR) of the enrolled cohort measured by RECIST v1.1 and iRECIST.	ORR by RECIST v1.1 and iRECIST.	18 months
Evaluate the median progression-free survival (PFS) of the enrolled cohort measured by RECIST v1.1 and iRECIST.	PFS by RECIST v1.1 and iRECIST.	18 months
Correlation between the baseline composition of the intestinal microbiome with PFS.	Microbiome composition through 16S rRNA sequencing with PFS by RECIST v1.1 and iRECIST.	18 months
Correlation between the baseline composition of the intestinal microbiome with ORR.	Microbiome composition through 16S rRNA sequencing with ORR by RECIST v1.1 and iRECIST.	18 months
Correlation between the baseline autoimmune panels with ORR.	Correlate the reactivity of baseline auto-antibodies detected through the 162 IgM and IgG antigen microarray with ORR per RECIST v1.1 and iRECIST.	18 months
Correlation between the baseline autoimmune panels with PFS.	Correlate the reactivity of baseline auto-antibodies detected through the 162 IgM and IgG antigen microarray with PFS per RECIST v1.1 and iRECIST.	18 months
Correlation between the change in composition of the intestinal microbiome at multiple time-points with ORR.	Change in microbiome composition as outlined above with ORR per RECIST v1.1 and iRECIST.	18 months
Correlation between the change in composition of the intestinal microbiome at multiple time-points with PFS.	Change in microbiome composition as outlined above with PFS per RECIST v1.1 and iRECIST.	18 months
Correlation between the change in autoimmune panels at multiple time-points with ORR.	Change in reactivity of auto-immune antibodies as outlined above with ORR per RECIST v1.1 and iRECIST.	18 months
Correlation between the change in autoimmune panels at multiple time-points with PFS.	Change in reactivity of auto-immune antibodies as outlined above with PFS per RECIST v1.1 and iRECIST.	18 months
Correlation between the composition of the intestinal microbiome at different time-points with radiomic analysis using voxels lying inside the tumor volume of interest.	Correlation of bacteria taxa composition through 16S rRNA sequencing with radiomic analysis.	18 months
Correlation between the reactivity of autoimmune panels at different time-points with radiomic analysis using voxels lying inside the tumor volume of interest.	Correlation of auto-immune antibodies as outlined above with radiomic analysis	18 months

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Anna Spreafico, MD, Princess Margaret Cancer Centre

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2019
• Primary Completion (Estimated): March 5, 2025
• Study Completion (Estimated): March 5, 2025

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: September 26, 2019
• First Posted (Actual): September 27, 2019

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: solid tumor; immunooncology
• Other Study ID Numbers: INSPECT-IO-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No