Tofacitinib for the Treatment of Refractory Immune-related Colitis from Checkpoint Inhibitor Therapy- TRICK Study

Inclusion Criteria:

1. 18 years of age or older.

2. Able to provide informed consent.

3. Diagnosis of a solid tumor treated with an immune checkpoint inhibitor (ICI), withthe exception of colorectal cancer.

4. Exposure to an ICI (CTLA-4, PD-1, PDL-1) as part of a cancer treatment regimenwithin 6 months of the onset of colitis symptoms. The ICI may be used as a singleagent, or in combination with other ICIs, or with chemotherapy.

5. Current diagnosis of immune-related colitis characterized by grade ≥ 2 diarrhea asper CTCAE v5.0.

6. Patients should have failed corticosteroids (at least 1mg/kg equivalent ofprednisone for a minimum of 72 hours), and at least one dose of a biologic agent (i.e. either a TNFα inhibitor or an anti-integrin). Failure is defined as havingongoing grade ≥ 2 diarrhea per CTCAE v5.0.

7. Adequate hematological function, defined by:

8. hemoglobin ≥ 90 g/L

9. absolute neutrophil count ≥ 1.0 x 109/L

10. lymphocyte count ≥ 0.5 x 109/L

11. platelets ≥ 75 x 109/L

12. PT, PTT, INR ≤ 1.5 x upper limit of normal (ULN).

13. Adequate liver function, as assessed by the Child Pugh classification score (appendix 1). Patients with scores A and B are eligible for enrollment. Patientswith severe hepatic impairment (Child Pugh C) are excluded from the study.

14. Adequate renal function as defined by an estimated clearance ≥ 40 mL/min, calculatedper the Cockroft-Gault formula (appendix 2).

15. Women of childbearing potential (WOCBP) are eligible if they agree to use adequatecontraception while on study. If in line with the patient's preference and usuallifestyle, complete abstinence from heterosexual intercourse is acceptable. WOCBPmust otherwise agree to correctly and consistently use at least one "highlyeffective" in addition to one "effective" contraceptive methods:

Highly effective means of contraception include the following:

• Hormonal methods of contraception including combined oral contraceptives, vaginalring, injectables, patch, implants, and intrauterine systems (IUSs).

• Nonhormonal intrauterine devices (IUDs).

• Tubal ligation

• Vasectomy of the sole partner of a female subject

• Male condoms with spermicide

Effective means of contraception include the following:

• Diaphragm with spermicide

• Cervical cap with spermicide

• Vaginal contraceptive sponge

• Male condom without spermicide

• Female condom (a male and female condom must not be used together)

Exclusion criteria:

1. Diagnosis of a thromboembolic event (deep vein thrombosis, pulmonary embolism,embolic stroke, myocardial infarction, or peripheral arterial insufficiency) within 3 months of enrollment.

2. Diagnosis of concomitant infectious colitis (e.g. C. difficile or other bacterialsource), unless the patient has finished an appropriate length of treatment withantibiotics as indicated for each diagnosis at the time of enrollment.

3. Any other grade ≥ 3 infection at the time of enrollment.

4. Prior therapy with a JAK inhibitor within 3 months preceding enrollment.

5. Use of strong inducers of CYP3A4 within 7 days of starting treatment withtofacitinib (see appendix 3).

6. Known allergy or hypersensitivity to tofacitinib, its excipients or any of the drugsused in this study (valacyclovir, heparin, trimethoprim and sulfonamides).

7. Active pregnancy or breastfeeding.

8. Patients on intravenous biologic agents for other baseline autoimmune conditions.

9. Patients having other concomitant uncontrolled irAEs at the time of enrollment whichwould require systemic corticosteroids or biologic immunomodulatory agents.