Vedolizumab for the Prevention of ICI Related Diarrhea or Colitis in Patients With Cancer

VERIFY is a multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group superiority trial, evaluating the efficacy and safety of vedolizumab, a monoclonal antibody targeting the α4β7 integrin receptor specific to gut-targeted T-lymphocytes, for the prevention of ICI-related diarrhea and colitis in participants with unresectable melanoma, lung, or renal cancer starting immunotherapy who are at high risk, defined by the development of an elevated fecal calprotectin >100 μg/g within 4 weeks of the first ICI dose.

Eligible participants will be randomized 1:1 to receive 6 months of vedolizumab or placebo, administered as prophylaxis therapy in addition to continuing ICI treatment (administered at weeks 0, 2, 6, 14, and 22). Participants will then be followed for 1 year.

• Vedolizumab (Biological): 300 mg IV at weeks Baseline (Week 0) Weeks 2, 6, 14, and 22.
• Placebo (Biological): 300 mg IV at Baseline (Week 0) Weeks 2, 6, 14, and 22.

Primary outcomes

• To establish the feasibility of the VERIFY protocol and determine progression to the full trial [Up to 5 years]: Feasibility defined by achievement of all pre-specified progression criteria: * Recruitment >75% target (>0.53 participants per site per month achieving randomization) * Recruitment: fecal calprotectin after first dose of ICI therapy >100 μg/g in at least 15% of screened participants * Protocol adherence: >95% of randomized participants receiving allocated treatment, protocol adherence in >90% * Outcome data quality: endoscopy and biopsies taken in >90% of eligible participants, <10% loss to follow-up * Feedback: no major concerns identified by patients or providers on acceptability survey * >15% of placebo-treated participants developing the primary outcome (sufficient event rate for feasible prevention) * Rate of PFS and OS is not lower than historical estimates from a similar population

Secondary outcomes

• To evaluate feasibility of recruitment [Up to 5 years]: • Mean time to site initiation
• To evaluate feasibility of recruitment [Up to 5 years]: • Number of screened participants
• To evaluate feasibility of recruitment [Up to 5 years]: • Screen failure rate and qualitative assessment of reasons for screen failure
• To evaluate feasibility of recruitment [Up to 5 years]: • Qualitative assessment of reasons for screen failure
• To evaluate feasibility of adhering to the protocol [Up to 5 years]: Adherence feasibility metrics will include: * Proportion of participants receiving the allocated treatment within 2 weeks of randomization * Proportion of participants adhering to the follow-up schedule
• To evaluate feasibility of adhering to the protocol [Up to 5 years]: Adherence feasibility metrics will include: • Number and qualitative description of minor and major protocol deviations
• To evaluate feasibility of obtaining high quality outcome data [Up to 5 years]: Outcome measure feasibility metrics will include: * Proportion of eligible participants undergoing lower endoscopy and biopsies to confirm histologic ICI-related colitis * Proportion of participants lost to follow-up and qualitative assessment of reasons for loss to follow-up
• To evaluate the incidence of diarrhea and colitis in the placebo group [Up to 1 year]: Feasibility of prevention metrics will include: * Proportion of participants receiving placebo who develop CTCAE grade ≥2 diarrhea/colitis * Proportion of participants receiving placebo who develop CTCAE grade ≥3 diarrhea/colitis * Proportion of participants receiving placebo who develop CTCAE any grade diarrhea/colitis
• To evaluate the efficacy of concomitant vedolizumab and ICI therapy [Up to 1 year]: To ensure that there is no interaction between vedolizumab and efficacy of ICI therapy, evaluation will include: • Progression free survival and overall survival in the vedolizumab group (compared to a historical control population)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Signed informed consent prior to initiation of any study specific activities or procedures
2. Adult patient ≥18 years old
3. Diagnosed with unresectable advanced stage III or metastatic stage IV malignant melanoma, lung, or renal cancer
4. Planned for initiation of SOC treatment with any immunotherapy and develop an elevated fecal calprotectin > 100 μg/g within 4 weeks of first ICI dose
5. Ability to and willingness to adhere to the randomized treatment interventions (vedolizumab or placebo), administered intravenously
6. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.
7. As per the Health Canada product monograph, WOCBP are strongly recommended to use adequate contraception to prevent pregnancy and to continue its use for at least 6 months after the last study visit.

Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.

Exclusion Criteria:

1. Condition(s) for which vedolizumab is contraindicated (e.g., hypersensitivity reaction, known allergic reaction to vedolizumab or its components)
2. Current or prior use of vedolizumab
3. Presence of inflammatory bowel disease (Crohn's disease, ulcerative colitis), indeterminate colitis, segmental colitis associated with diverticulosis or microscopic colitis
4. Presence of ileostomy, colostomy, or short bowel syndrome
5. Presence of known luminal gastrointestinal metastases at baseline
6. Presence of significant pre-existing autoimmune disease (at investigator's discretion)
7. Presence of severe infection(s) or opportunistic infection(s)
8. Active enteric infection with viral, bacterial, or parasitic pathogens
9. Presence of untreated latent or active tuberculosis, or untreated chronic hepatitis B virus. If there is a clinical suspicion of either, it is at the discretion of the Investigator to order the appropriate work-up.
10. Baseline ECOG status grade ≥3
11. Pregnancy or lactation (no exclusion for pregnant partner)
12. Treatment with another investigational product within 8 weeks of randomization
13. Requirement for baseline anti-diarrheal treatment(s) (including but not limited to loperamide, diphenoxylate-atropine, octreotide, tincture of opium), anticholinergic drug(s), or opioid-based analgesic(s) used specifically for diarrhea control within 14 days of randomization
14. Any condition or diagnosis, that could in the opinion of the Qualified Investigator or delegate interfere with the participant's ability to comply with study instructions, might confound the interpretation of the study results, or put the participant at risk