sponsor decision, due to low recruitment rate

This is a single-arm pilot study evaluating the efficacy and safety of tofacitinib in cancer patients with immune-related colitis from immune checkpoint inhibitor (ICI) therapy.

Primary objective and endpoint

• Efficacy of tofacitinib in inducing clinical remission of immune related colitis, as measured by the proportion of patients who experience diarrhea resolution to grade ≤1 as per Common Terminology Criteria for Adverse Events [CTCAE] v5.0) without the requirement for additional immunosuppression (e.g., corticosteroids, biologics, or other immunosuppressors targeted for colitis) 8 weeks post-first dose of tofacitinib.

Secondary objectives and endpoints:

• Safety of tofacitinib in cancer patients with immune-related colitis, as defined by the occurrence of adverse events grade ≥3.
• Efficacy of tofacitinib in cancer patients with immune colitis as defined by endoscopic remission of colitis (a total Mayo score of ≤2) at 8 weeks.
• Efficacy of tofacitinib to induce a clinical remission of immune-related colitis as measured by the time, in days, necessary to achieve a diarrhea of grade ≤ 1 (as per CTCAE v 5.0).
• Number of patients with tumor progression at 8 weeks per iRECIST and RECIST 1.1 criteria compared to baseline scans.

Exploratory objective

• The study will collect blood samples from participants seeking to characterize the inflammatory landscape of ICI-mediated colitis and biomarkers predictive of response to tofacitinib.

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), with the exception of colorectal cancer.

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

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

6. Patients should have failed corticosteroids (at least 1mg/kg equivalent of prednisone 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 having ongoing grade ≥ 2 diarrhea per CTCAE v5.0.

7. Adequate hematological function, defined by:

   1. hemoglobin ≥ 90 g/L
   2. absolute neutrophil count ≥ 1.0 x 109/L
   3. lymphocyte count ≥ 0.5 x 109/L
   4. platelets ≥ 75 x 109/L
   5. PT, PTT, INR ≤ 1.5 x upper limit of normal (ULN).

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

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

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

Highly effective means of contraception include the following:

• Hormonal methods of contraception including combined oral contraceptives, vaginal ring, 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 bacterial source), unless the patient has finished an appropriate length of treatment with antibiotics 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 with tofacitinib (see appendix 3).
6. Known allergy or hypersensitivity to tofacitinib, its excipients or any of the drugs used 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 which would require systemic corticosteroids or biologic immunomodulatory agents.