Infliximab for Treatment of Ipilimumab Colitis

Sponsor
Massachusetts General Hospital (Other)
Overall Status
Recruiting
CT.gov ID
NCT04305145
Collaborator
(none)
42
2
3
33.9
21
0.6

Study Details

Study Description

Brief Summary

This research study is evaluating the effectiveness and safety of infliximab therapy compared with steroids in the treatment of ipilimumab-induced colitis in patients with III/IV melanoma.

Detailed Description

This is a phase II, randomized, signal-detection trial to evaluate the efficacy and safety of the drugs Infliximab, Methylprednisolone and prednisone to manage the side of effect of colitis from the standard of care drug ipilimumab

The names of the study drugs involved in this study are:
  • Infliximab

  • Methylprednisolone

  • Prednisone

Participants will receive ipilimumab and any other cancer treatments per standard of care for stage III/IV melanoma at the discretion of treating oncologist.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

Participants are expected to be on study treatment for up to 7 weeks and followed every to 6 months as agreed.

It is expected that about 42 people will take part in this research study.

The FDA has approved infliximab, methylprednisolone, and prednisone as treatment options for colitis.

Patients will also receive ipilimumab as part of the standard of care for stage III/IV melanoma.

The U.S. Food and Drug Administration (FDA) has approved ipilimumab as a treatment option for III/IV melanoma.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
42 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Study of Infliximab for the Treatment of Ipilimumab Colitis
Actual Study Start Date :
Aug 31, 2020
Anticipated Primary Completion Date :
Jun 30, 2023
Anticipated Study Completion Date :
Jun 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Infliximab

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Infliximab: Predetermined intravenous single dose, up to 3 doses over 7 weeks. Cross over for inadequate response -- Patients who do not respond to initial treatment within 3 days with a decrease in symptoms by one grade, or who do not improve to grade 2 or less symptoms by 5 days will add combination therapy from the other treatment arm at full initial dosing

Drug: Infliximab
Infusion
Other Names:
  • AVSOLA
  • Ixifi
  • Remicade
  • Renflexis
  • Experimental: Inpatient

    The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. methylprednisone-Predetermined intravenous dose, 2x daily up to 7 weeks prednisone Oral daily predetermined dose Cross over for inadequate response -- Patients who do not respond to initial treatment within 3 days with a decrease in symptoms by one grade, or who do not improve to grade 2 or less symptoms by 5 days will add combination therapy from the other treatment arm at full initial dosing

    Drug: Methylprednisolone
    Infusion
    Other Names:
  • Solu-Medrol
  • Duralone
  • Medralone
  • Medrol
  • M-Prednisol
  • Drug: Prednisone
    Orally
    Other Names:
  • Deltasone
  • Prednicot
  • predniSONE Intensol
  • Rayos
  • Sterapred
  • Sterapred DS
  • Experimental: Outpatient

    The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits Prednisone Predetermined oral dose, 2x daily up to 7 weeks Cross over for inadequate response -- Patients who do not respond to initial treatment within 3 days with a decrease in symptoms by one grade, or who do not improve to grade 2 or less symptoms by 5 days will add combination therapy from the other treatment arm at full initial dosing

    Drug: Prednisone
    Orally
    Other Names:
  • Deltasone
  • Prednicot
  • predniSONE Intensol
  • Rayos
  • Sterapred
  • Sterapred DS
  • Outcome Measures

    Primary Outcome Measures

    1. Proportion of patients with Steroid-Free Colitis [7 weeks]

      Proportion of Patients with Steroid-Free Colitis at seven weeks with steroid-free colitis remission defined as less than 7.5 mg a day of prednisone or equivalent and grade-1 or lower symptoms.

    Secondary Outcome Measures

    1. Proportion of Participants with Treatment Related Adverse Events as Assessed by CTCAE 5. [6 Months]

      National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

    2. The proportion of patients requiring secondary immune suppression-Infliximab [7 Weeks]

      patients randomly assigned to infliximab, secondary immune support will be defined as requiring subsequent treatment with steroids. The proportions of patients in each treatment arm requiring secondary immune suppression will be summarized and presented with 90% exact binomial confidence intervals

    3. The proportion of patients requiring secondary immune suppression-Steroids [7 Weeks]

      patients randomly assigned to steroids, secondary immune support will be defined as requiring subsequent treatment with steroids. The proportions of patients in each treatment arm requiring secondary immune suppression will be summarized and presented with 90% exact binomial confidence intervals

    4. Time to steroid-free remission [randomization to grade-1 or lower symptoms of colitis and less than 7.5 mg a day of prednisone or equivalent or up to 6 months]

      The initial analysis of steroid-free remission will be based on cumulative incidence (1-Kaplan-Meier estimates).

    5. Rate of Symptom Remission at 72 hours [72 hours]

      The proportion of patients in each treatment arm who have colitis symptom reduction to grade-1 or less within 72 hours of starting randomized treatment will be summarized and presented with 90% exact binomial confidence intervals. The treatment arms will be compared using Fisher's exact tests.

    6. Rate of Symptom Remission at 4 Weeks [4 weeks]

      The proportion of patients in each treatment arm who have colitis symptom reduction to grade-1 or less within 72 hours of starting randomized treatment will be summarized and presented with 90% exact binomial confidence intervals. The treatment arms will be compared using Fisher's exact tests.

    7. Proportion of patients with colectomy or colitis-specific mortality [7 weeks]

      The proportions of patients with colectomy or colitis-specific mortality (investigator assessed) will be presented by treatment arm with 90% exact binomial confidence intervals

    8. Cumulative steroid exposure [7 weeks]

      Cumulative steroid exposure over time for each patient will be calculated by adding the number of doses multiplied by strength of dose over the total follow-up time. Steroid exposure will be summarized descriptively for each treatment arm, and compared using a Wilcoxon rank-sum test. With 20 patients per treatment arm, a Wilcoxon rank-sum test will have 80% power to detect a 41difference in cumulative steroid exposure that is 0.85 times the common standard deviation, assuming a one-sided, type-I error of 10

    9. Progression Free Survival [duration of time from start of randomization to time of progression or death, whichever occurs first or up to 24 months.]

      summarized using the method of Kaplan-Meier and compared using stratified log-rank tests

    10. Overall Survival [the duration of time from start of randomization to time of death or up to 24 months]

      summarized using the method of Kaplan-Meier and compared using stratified log-rank tests

    11. Overall Response Rate [proportion of evaluable patients who achieve either a (complete response) CR or (partial response) PR or up to 24 Months]

      Response rates will be summarized by treatment arm and presented with 90% exact binomial confidence intervals. The comparison of response rates between treatment arms will use Fisher's exact test

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Age ≥ 18

    • Stage III/IV melanoma

    • Treatment with ipilimumab or ipilimumab in combination with PD-1or PD-L1 blockade within the past 8 weeks; investigational combinations will be permitted provided that they include ipilimumab and a drug targeting PD-1 and/or PD-L1

    • Meets eligibility requires for treatment with ipilimumab

    • Patients with brain metastases and who have received radiation are eligible

    • Prior treatment with targeted or alternative immunotherapy is allowed, provided that these medications were discontinued prior to initiation of the current ipilimumab containing treatment regimen

    • Grade 2-4 diarrhea by Common Terminology Criteria for Adverse Events (CTCAE) onset after treatment

    • Prior to randomization, endoscopically determined colitis, according to Mayo Scoring system, score of 1-3

    • Patients will be permitted to have received up to 3 doses of systemic corticosteroids within 72 hours (up to a maximum dose of 2 mg/kg) prior to endoscopy and randomization

    • Hepatitis B surface antigen, surface antibody, and core antibody must be sent but will not need to be resulted prior to enrollment

    Exclusion Criteria:
    • Prior history of inflammatory colitis related to immune checkpoint inhibitors requiring treatment with > 10 mg/day of prednisone or equivalent, or any other immunosuppressive medication

    • Concurrent immune-related Adverse Event (irAE) requiring treatment with systemic corticosteroids (dose equivalent of prednisone 10 mg/day or higher) or another systemic immune suppressing medication within the past 10 days

    • Current use of any immune suppressing biologic medication, or use within the last 4 weeks; immune stimulating medications such as checkpoint blockade are explicitly permitted

    • Current use of combination treatment with an investigation immunotherapy targeting a pathway other than PD-1 or PD-L1, concurrent chemotherapy, or targeted therapy

    • Previous adverse reaction to infliximab or corticosteroids

    • Colonic perforation or abscess

    • History of Hepatitis B or C with a positive viral load, untreated mycobacterium tuberculosis, or active herpes zoster infection; current negative testing results will not be required to be sent prior to study enrollment

    • Positive testing for C Difficile or another colonic infection

    • Current bacterial infection requiring antibiotic treatment, or systemic fungal infection

    • Prior history of inflammatory bowel disease, microscopic colitis or segmental colitis associated with diverticulosis

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 02114
    2 Dana-Farber Cancer Institute Boston Massachusetts United States 02215

    Sponsors and Collaborators

    • Massachusetts General Hospital

    Investigators

    • Principal Investigator: Michael Dougan, MD, PHD, Massachusetts General Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Michael Dougan, Principal Investigator, Massachusetts General Hospital
    ClinicalTrials.gov Identifier:
    NCT04305145
    Other Study ID Numbers:
    • 19-763
    First Posted:
    Mar 12, 2020
    Last Update Posted:
    Oct 28, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Michael Dougan, Principal Investigator, Massachusetts General Hospital
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Oct 28, 2021