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Infliximab for Treatment of Ipilimumab Colitis

Primary Purpose

Melanoma Stage III, Melanoma Stage IV, Side Effect of Drug

Status

Unknown status

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Infliximab

Methylprednisolone

Prednisone

About this trial

This is an interventional treatment trial for Melanoma Stage III focused on measuring Melanoma Stage III, Melanoma Stage IV, Side Effect of Drug, Colitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Massachusetts General Hospital Cancer CenterRecruiting
Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Infliximab

Inpatient

Outpatient

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Proportion of patients with Steroid-Free Colitis

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

Proportion of Participants with Treatment Related Adverse Events as Assessed by CTCAE 5.

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

The proportion of patients requiring secondary immune suppression-Infliximab

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

The proportion of patients requiring secondary immune suppression-Steroids

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

Time to steroid-free remission

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

Rate of Symptom Remission at 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.

Rate of Symptom Remission at 4 Weeks

Proportion of patients with colectomy or colitis-specific mortality

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

Cumulative steroid exposure

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

Progression Free Survival

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

Overall Survival

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

Overall Response Rate

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

Full Information

NCT ID

NCT04305145

First Posted

March 9, 2020

Last Updated

October 26, 2021

Sponsor

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04305145

Brief Title

Infliximab for Treatment of Ipilimumab Colitis

Official Title

Phase II Study of Infliximab for the Treatment of Ipilimumab Colitis

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Unknown status

Study Start Date

August 31, 2020 (Actual)

Primary Completion Date

June 30, 2023 (Anticipated)

Study Completion Date

June 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma Stage III, Melanoma Stage IV, Side Effect of Drug, Colitis

Keywords

Melanoma Stage III, Melanoma Stage IV, Side Effect of Drug, Colitis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

42 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Infliximab

Arm Type

Experimental

Arm Description

Arm Title

Inpatient

Arm Type

Experimental

Arm Description

Arm Title

Outpatient

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Infliximab

Other Intervention Name(s)

AVSOLA, Ixifi, Remicade, Renflexis

Intervention Description

Infusion

Intervention Type

Drug

Intervention Name(s)

Methylprednisolone

Other Intervention Name(s)

Solu-Medrol, Duralone, Medralone, Medrol, M-Prednisol

Intervention Description

Infusion

Intervention Type

Drug

Intervention Name(s)

Prednisone

Other Intervention Name(s)

Deltasone, Prednicot, predniSONE Intensol, Rayos, Sterapred, Sterapred DS

Intervention Description

Orally

Primary Outcome Measure Information:

Title

Proportion of patients with Steroid-Free Colitis

Description

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.

Time Frame

7 weeks

Secondary Outcome Measure Information:

Title

Proportion of Participants with Treatment Related Adverse Events as Assessed by CTCAE 5.

Description

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

Time Frame

6 Months

Title

The proportion of patients requiring secondary immune suppression-Infliximab

Description

Time Frame

7 Weeks

Title

The proportion of patients requiring secondary immune suppression-Steroids

Description

Time Frame

7 Weeks

Title

Time to steroid-free remission

Description

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

Time Frame

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

Title

Rate of Symptom Remission at 72 hours

Description

Time Frame

72 hours

Title

Rate of Symptom Remission at 4 Weeks

Description

Time Frame

4 weeks

Title

Proportion of patients with colectomy or colitis-specific mortality

Description

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

Time Frame

7 weeks

Title

Cumulative steroid exposure

Description

Time Frame

7 weeks

Title

Progression Free Survival

Description

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

Time Frame

duration of time from start of randomization to time of progression or death, whichever occurs first or up to 24 months.

Title

Overall Survival

Description

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

Time Frame

the duration of time from start of randomization to time of death or up to 24 months

Title

Overall Response Rate

Description

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

Time Frame

proportion of evaluable patients who achieve either a (complete response) CR or (partial response) PR or up to 24 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Michael Dougan, MD, PHD

Phone

617-726-3527

Michael_Dougan@DFCI.HARVARD.EDU

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael Dougan, MD, PHD

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital Cancer Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michael Dougan, MD, PhD

Phone

617-726-3527

Michael_Dougan@DFCI.HARVARD.EDU

Facility Name

Dana-Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Elizabeth Buchbinder, MD

Phone

617-632-5055

Elizabeth_buchbinder@dfci.harvard.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

IPD Sharing Time Frame

Data can be shared no earlier than 1 year following the date of publication

IPD Sharing Access Criteria

Massachusetts General Hospital (MGH) - Contact the Partners Innovations team at http://www.partners.org/innovation

Learn more about this trial

Infliximab for Treatment of Ipilimumab Colitis

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