Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis

NCT05947669 | Recruiting Phase 3 DMC

• 1 other identifier: The ICaD Study
• Study Type: interventional
• Target: 195
• Locations: 2 countries
• Sites: 3

Brief Summary

The goal of this clinical trial is to assess whether the early introduction of biological treatment with a TNF-alpha inhibitor (infliximab) in addition to corticosteroids for severe ir-colitis/diarrhoea will reduce the time to grade ≤ 1 ir-colitis/diarrhoea compared to corticosteroids alone in patients scheduled for ICI treatment for solid tumors and untreated mCTCAE grade 2-4 diarrhoea or colitis. The main question it aims to answer is: • Can an early introduction of biological treatment with a TNF-alpha inhibitor (infliximab) in addition to corticosteroids reduce the time to grade ≤ 1 ir-colitis/diarrhoea compared to corticosteroids alone. Participants will be randomised 1:1: Arm A: All patients will receive same dose of methylprednisolone i.v. daily. Arm B: Patients allocated to Arm B will in addition receive infliximab i.v. day 1 or 2. Study patients are evaluated with blood samples, faecal samples and by sigmoidoscopy. Procedures are performed before randomisation and as part of follow up.

Conditions

Colitis

Outcome Measures

Primary Outcomes (1)

• Time (days) to persistent modified CTCAE grade ≤ 1 ir-colitis/diarrhoea.

  Persistent is defined as grade ≤ 1 ir-colitis/diarrhoea for five consecutive days or more with no increase in corticosteroid intake

  From the first day of grade ≤ 1 ir-colitis/diarrhoea of that period (time frame: seven weeks)

Secondary Outcomes (9)

• Proportion of study subjects with grade ≤ 1 ir-colitis/diarrhoea at 72 hours.

  Time frame: 72 hours

• Proportion of study subjects with persistent grade ≤ 1 ir-colitis/diarrhoea at three weeks.

  The event will be calculated from the first day of grade ≤ 1 ir-colitis/diarrhoea of that period (time frame: three weeks)

• Proportion of study subjects with a corticosteroid-free clinical remission (grade ≤ 1 ir-colitis/diarrhoea) after seven weeks.

  Time frame: seven weeks

• Proportion of study subjects requiring rescue immunosuppressive medication

  Time frame: seven days

• Cumulative corticosteroid exposure

  Time frame: seven weeks

Other Outcomes (4)

• Proportion of study subjects with recurrence of ir-colitis/diarrhoea on subsequent reintroduction of ICI.

  Timeframe: Up to 24 weeks

• Subgroup analyses stratified for ipilimumab containing ICI for time (days) to persistent grade ≤ 1 ir-colitis/diarrhoea.

  week 3

• Progression Free Survival stratified by cancer type

  Time frame: duration of time from start of randomisation to time of progression or death, whichever occurs first or up to 24 months

Study Arms (2)

Standard of care - Methylprednisolone

ACTIVE COMPARATOR

Subjects are hospitalised Day 1 and for at least 4 days. It is accepted that participating centres handle the subjects on an outpatient basis as long as all study requirements are met. Methylprednisolone 80 mg intravenously (body weight 40-80 kg; methylprednisolone 1 mg/kg if body weight \< 40 or \> 80 kg) will be administered from Day 1 until mCTCAE ir-colitis/diarrhoea grade ≤ 2 and hereafter converted to oral prednisolone. During tapering, if ir-colitis/diarrhoea increases from grade 2 to ≥ grade 3, or from grade \< 2 to ≥ grade 2, re-assessment including diagnostic workup will be performed, and the patient will be evaluated for rescue infliximab.

Drug: Methylprednisolone; Drug: Prednisolone

Treatment with infliximab

EXPERIMENTAL

Infliximab will be administered Day 1 or latest Day 2 (within 48 hours). Infliximab infusion is handled as standard by skilled staff. A second dose of infliximab will be administered if ir-colitis/diarrhoea has not resolved to grade ≤ 2 on Day 7. Methylprednisolone 80 mg (body weight 40-80 kg; methylprednisolone 1 mg/kg if body weight \< 40 or \> 80 kg) intravenously is co-administered from Day 1 until mCTCAE ir-colitis/diarrhoea grade ≤ 2 and hereafter converted to oral prednisolone. Initial dosage of infliximab is 5 mg/kg. Dosage of infliximab for subjects referred to a second dose of infliximab will be left to the discretion of the treating physician. In the event of failure of infliximab, second line biological immunosuppressant treatment will also be left to the discretion of the treating physician.

Drug: Infliximab; Drug: Methylprednisolone; Drug: Prednisolone

Interventions

Infliximab DRUG

Infliximab is available in vials of 100 mg with pharmaceutical form of concentrate for solution for infusion. Participating sites will ensure availability of infliximab as part of the hospital's standard supply for use in the study.

Treatment with infliximab

Methylprednisolone DRUG

Methylprednisolone is available in vials of 40 mg. Methylprednisolone is a drug used for standard treatment first line for ir-colitis or diarrhoea CTCAE grade ≥ 3. Participating sites will ensure availability of methylprednisolone for use in the study as part of the hospitals standard supply.

Standard of care - Methylprednisolone; Treatment with infliximab

Prednisolone DRUG

Prednisolone is available in tablets of 25 or 5 mg. Oral corticosteroids are internationally recommended as initial treatment for ir-colitis and ir-diarrhoea CTCAE grade 2 \[24-27\]. Participating sites will ensure availability of prednisolone for use in the study as part of the hospitals' standard supply.

Standard of care - Methylprednisolone; Treatment with infliximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Untreated mCTCAE grade 2-4 diarrhoea or colitis, or persistent mCTCAE grade 2 diarrhoea after administration of loperamide or equivalent for mCTCAE grade ≤ 2 diarrhoea
• No signs of colonic perforation or infection
• Age ≥ 18
• Understands the nature and purpose of the study and the study procedures and has signed informed consent
• Is able to read, understand, and complete questionnaires and daily components of the patient Diary for the study period
• Histologically confirmed malignant solid tumours
• Treatment with immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1 or anti-PD-L1) within the past 12 weeks. Immune checkpoint inhibitors can be administered as single agents or as combination therapy with anti-CTLA-4 and anti-PD-1
• No probability of a concomitant treatment (e.g. laxatives) other than the immune checkpoint inhibitor being the causal drug for the colitis or diarrhoea
• Prior treatment with immune checkpoint inhibitors is allowed
• Usage of prednisolone ≤ 10 mg daily for non irAE is allowed
• Diagnostic work up including screening for viral hepatic infection and QuantiFERON-TB for mycobacterium tuberculosis must be requisitioned but will not need to be reported prior to study enrolment
• Women of child bearing potential must have a negative serum (preferred) or urine pregnancy test within 72 hours prior to registration.
• Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.
• Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the study treatment:
• for at least 6 months after the last study treatment, or depending on the duration antineoplastic treatment

You may not qualify if:

• Prior history of inflammatory bowel disease, colitis, or diarrhoea requiring treatment with any corticosteroid, or any other immunosuppressant medication
• Prior history of recurrent bowel disease including symptomatic diverticulosis
• Current positive testing for Clostridium difficile or other colonic infection
• Current bacterial infection requiring antibiotic treatment, or systemic fungal infection
• Ongoing antibiotic treatment for any reason
• Treatment with systemic corticosteroids within the last four weeks prior to study enrolment (daily usage of prednisolone ≤ 10 mg for non irAE conditions is accepted)
• Concurrent immune-related adverse events requiring immunosuppressant medication of any kind
• Known hypersensitivity or contraindications to systemic corticosteroids or infliximab
• Prior history of viral hepatitis with a positive viral load, known untreated mycobacterium tuberculosis, or known active herpes zoster infection

Sponsors & Collaborators

• Odense University Hospital: lead
• Aalborg University Hospital: collaborator
• Royal Marsden NHS Foundation Trust: collaborator

Study Sites (3)

Department of Oncology, Aalborg University Hospital

Aalborg, Denmark

NOT YET RECRUITING

Department of Oncology Odense University Hospital

Odense, Denmark

RECRUITING

The Royal Marsden Hospital

London, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Colitis

Interventions

Infliximab; Methylprednisolone; Prednisolone

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Christina H. Ruhlmann, PhD

  Department of Oncology, OUH

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sören K. Petersen, MD

CONTACT

0045 2046 5726; soeren.kjaer@rsyd.dk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2023
• First Posted: July 17, 2023
• Study Start: August 22, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2028
• Last Updated: August 24, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: No later than one year after the trial has ended.

Locations

DK (2); GB (1)