Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis

NCT ID: NCT05947669

Last Updated: 2023-08-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 195 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-22
• Study Completion Date: 2028-09-30

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of care - Methylprednisolone

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.

Group Type: ACTIVE_COMPARATOR

Methylprednisolone

Intervention Type: 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.

Prednisolone

Intervention Type: 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.

Treatment with infliximab

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.

Group Type: EXPERIMENTAL

Infliximab

Intervention Type: 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.

Methylprednisolone

Intervention Type: 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.

Prednisolone

Intervention Type: 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.

Interventions

Infliximab

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.

Intervention Type: DRUG

Methylprednisolone

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.

Intervention Type: DRUG

Prednisolone

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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
• Note: A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aalborg University Hospital

OTHER

Sponsor Role: collaborator

Royal Marsden NHS Foundation Trust

OTHER

Sponsor Role: collaborator

Odense University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christina H. Ruhlmann, PhD

Role: PRINCIPAL_INVESTIGATOR

Department of Oncology, OUH

Locations

Department of Oncology, Aalborg University Hospital

Aalborg, , Denmark

Site Status: NOT_YET_RECRUITING

Department of Oncology Odense University Hospital

Odense, , Denmark

Site Status: RECRUITING

The Royal Marsden Hospital

London, , United Kingdom

Site Status: NOT_YET_RECRUITING

Countries

Denmark; United Kingdom

Central Contacts

Sören K. Petersen, MD

Role: CONTACT

soeren.kjaer@rsyd.dk

0045 2046 5726

Facility Contacts

Charlotte Aaquist Haslund, MD

Role: primary

Christina H. Ruhlmann, PhD

Role: primary

christina.ruhlmann@rsyd.dk

0045 2231 4446

Kate Young, MD

Role: primary

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

The ICaD Study

Identifier Type: -

Identifier Source: org_study_id