Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis

Colitis Clinical Trial

— iCaD  

Official title:

Efficacy and Safety of Infliximab for Immune Checkpoint Inhibitor Induced Colitis: a Multinational, Randomised, Open Label, Phase III Trial - The iCaD Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05947669
• Other study ID #: The ICaD Study
• Status: Recruiting
• Phase: Phase 3
• Start date: August 22, 2023
• Est. completion date: September 2028

Study information

• Verified date: August 2023
• Source: Odense University Hospital
• Contact: Sören K. Petersen, MD
• Phone: 0045 2046 5726
• Email: soeren.kjaer[@]rsyd.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 195
• Est. completion date: September 2028
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colitis

Intervention

Drug:
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Denmark	Department of Oncology, Aalborg University Hospital	Aalborg
Denmark	Department of Oncology Odense University Hospital	Odense
United Kingdom	The Royal Marsden Hospital	London

Sponsors (3)

Lead Sponsor	Collaborator
Odense University Hospital	Aalborg University Hospital, Royal Marsden NHS Foundation Trust

Countries where clinical trial is conducted

Denmark,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Proportion of study subjects with recurrence of ir-colitis/diarrhoea on subsequent reintroduction of ICI.		Timeframe: Up to 24 weeks
Other	Subgroup analyses stratified for ipilimumab containing ICI for time (days) to persistent grade = 1 ir-colitis/diarrhoea.	Persistent is defined as grade = 1 ir-colitis/diarrhoea for five consecutive days or more.	week 3
Other	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
Other	Overall Survival stratified by cancer type		Time frame: the duration of time from start of randomisation to time of death or up to 24 months
Primary	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	Proportion of study subjects with grade = 1 ir-colitis/diarrhoea at 72 hours.		Time frame: 72 hours
Secondary	Proportion of study subjects with persistent grade = 1 ir-colitis/diarrhoea at three weeks.	Persistent is defined as grade = 1 ir-colitis/diarrhoea for five consecutive days or more	The event will be calculated from the first day of grade = 1 ir-colitis/diarrhoea of that period (time frame: three weeks)
Secondary	Proportion of study subjects with a corticosteroid-free clinical remission (grade = 1 ir-colitis/diarrhoea) after seven weeks.		Time frame: seven weeks
Secondary	Proportion of study subjects requiring rescue immunosuppressive medication	Arm A (initial corticosteroid only): infliximab if no improvement to grade = 2 ir-colitis/diarrhoea after 3 days (time frame: seven weeks); Arm B (initial infliximab): second dose infliximab according to physicians decision if no improvement to grade = 2 ir-colitis/diarrhoea after seven days	Time frame: seven days
Secondary	Cumulative corticosteroid exposure		Time frame: seven weeks
Secondary	QoL by means of EORTC-QLQ-C30	A 30-item questionaire developed to assess the quality of life of cancer patients. Item 1-28 is scaled in a 4 scale score from 'not at all' to 'very much'. Item 29-30 is a numeric rating scale from 1 to 7 assessing overall health/quality of life. One denotes very poor and 7 denotes excellent.; Measure: changes in quality of life	Change in score from baseline to 3, 12, 24, and 52 weeks after randomisation
Secondary	QoL by means of selected PRO-CTCAE items	A 8 item questionnaire assessing bowel related issues. The scales ranges from eg: Yes/No Never/rarely/occasionally/frequently/almost constant None/mild/moderate/severe/very severe Not at all/a little bit/ somewhat/quit a bit/very much Measure: changes in bowel related symptoms	Change in score from baseline to 3, 12, 24, and 52 weeks after randomisation
Secondary	Proportion of study subjects with treatment related adverse events as assessed by CTCAE v5.0		Time frame: 12 weeks
Secondary	Proportion of study subjects with colectomy or colitis-specific mortality		Time frame: seven weeks