Methylprednisolone Sodium Succinate in Treating Patients With Acute Graft-versus-Host Disease of the Gastrointestinal Tract

Phase 2

Withdrawn

• Conditions: Acute Graft Versus Host Disease; Intestinal Graft Versus Host Disease
• Interventions: Drug: Budesonide; Drug: Methylprednisolone Sodium Succinate

• Registration Number: NCT02425813
• Lead Sponsor: Wake Forest University Health Sciences

Brief Summary

This phase II trial studies how well methylprednisolone sodium succinate works in treating patients with graft-versus-host disease (GVHD) of the gastrointestinal tract that has begun within 100 days of transplant (acute GVHD). Corticosteroids are a type of drug that reduces inflammation. Giving corticosteroid drugs, such as methylprednisolone sodium succinate, directly into the arteries of the gastrointestinal tract may help treat inflammation caused by GVHD. Giving methylprednisolone sodium succinate in addition to standard treatments may be more effective in treating GVHD.

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the efficacy of intra-arterial steroid administration (IASA) with methylprednisolone sodium succinate (MePDSL) in this dose-schedule for treatment of de novo acute moderate-to-severe GvHD of the gastrointestinal tract (GIT).

SECONDARY OBJECTIVES:

I. To assess the safety of IASA MePDSL in this dose-schedule for treatment of de novo acute moderate-to-severe acute GvHD of the GIT.

II. To assess the feasibility of IASA MePDSL in this dose-schedule for treatment of de novo acute moderate-to-severe acute GvHD of the GIT.

OUTLINE:

STUDY AGENT: Patients receive methylprednisolone sodium succinate intra-arterially (IA) once daily (QD) on days 1-3.

CONVENTIONAL THERAPY: Patients also receive conventional therapy comprising methylprednisolone sodium succinate intravenously (IV) every 12 hours on for 7-14 days beginning on day 1 and budesonide PO on days 1-56. Patients with response by day 7-14 may begin taper and receive methylprednisolone orally (PO) on days 28-56. Treatment continues in the absence of disease progression or unacceptable toxicity.

IMMUNOSUPPRESSIVE THERAPY (IST): Patients receive conventional IST or continue their previous prophylactic regimen beginning on day 1 to 56 (or beyond) at the discretion of the treating physician.

After completion of study treatment, patients are followed up for 360 days.

Study Timeline

• Study First Submitted: 2015-04-15
• Study First Submitted QC: 2015-04-21
• Study First Posted: 2015-04-24
• Study Start: 2015-10
• Primary Completion: 2016-07
• Study Completion: 2016-07
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-31
• Last Update Posted: 2018-08-02

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Diagnosis of acute GvHD of the GIT (any site except isolated "upper" GIT disease); other sites may be involved as well; their presence will not influence eligibility

  • Biopsies are strongly recommended and should be obtained, ideally, by full endoscopy including esophagogastroduodenoscopy (EGD) and flexible sigmoidoscopy or colonoscopy
  • However, and with an appropriate clinical presentation, it is desirable -- but not necessary -- to have pathology confirmation
  • If other diagnoses are excluded, it is not necessary to biopsy all potentially involved sites in the GIT to initiate therapy
  • It is possible that other diagnoses may be present as well, and this should not exclude eligibility so long as they are distinct (this statement is generic, but applies especially to various types of infective colitis; that said, on-going anti-infective therapy must be on-going)

• Any diagnosis, donor or source of hematopoietic stem cells (HSC) is allowed, including donor leukocyte infusions (DLI)

• Prior or on-going therapy:

  • De novo disease with no previous systemic (topical allowed) therapy for acute GvHD --except for a maximum (and ideally much less) of 72 hours of prior glucocorticoid (GC) therapy, > 0.5 mg/kg/day of MePDSL or equivalent after the onset of acute GvHD
  • An exception to the above exists for patients with prior acute GvHD (of any site) who received GC therapy, experienced a complete response (CR), were tapered off GC and recurred >= 15 days later; such are eligible after review by the principal investigator (PI) or his designee
  • The use of on-going acute GvHD prophylaxis will be continued
  • The use of any other IST is allowed if acute GvHD of the GIT develops while the patient is off all IST; IST may be started at the discretion of the attending physician after discussion with the PI of this study
  • Treatment with oral budesonide is to be started or continued at full dose
  • Please consult with the study PI regarding any questions or concerns of study eligibility

• No specific organ function parameters are required; however, significant abnormalities should be discussed with the study PI

• Ability to understand and the willingness to sign the Institutional Review Board (IRB)-approved informed consent document

Exclusion Criteria

• Significant risk factors for IASA therapy including, but not limited to: major uncorrectable coagulopathy, bowel perforation, ongoing bacteremia, mesenteric insufficiency, etc; in these or any questionable cases, discussion with the PI is recommended
• Patients may not be receiving any other drugs for the treatment of GvHD or investigational agents, except for a maximum of 72 hours of prior GC therapy, as above
• Uncontrolled, severe infective processes
• Patients with relapsed or persistent malignancy requiring immunosuppressive withdrawal or modulation (an example of this may be a patient who relapsed and was being treatment with DLI and then developed GvHD)
• Pregnant women are excluded from this study; breastfeeding should be discontinued

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (methylprednisolone sodium succinate, budesonide)	Methylprednisolone Sodium Succinate	STUDY AGENT: Patients receive methylprednisolone sodium succinate IA QD on days 1-3. CONVENTIONAL THERAPY: Patients also receive conventional therapy comprising methylprednisolone sodium succinate IV every 12 hours on for 7-14 days beginning on day 1 and budesonide PO on days 1-56. Patients with response by day 7-14 may begin taper and receive methylprednisolone PO on days 28-56. Treatment continues in the absence of disease progression or unacceptable toxicity. IST: Patients receive conventional IST or continue their previous prophylactic regimen beginning on day 1 to 56 (or beyond) at the discretion of the treating physician.
Treatment (methylprednisolone sodium succinate, budesonide)	Budesonide	STUDY AGENT: Patients receive methylprednisolone sodium succinate IA QD on days 1-3. CONVENTIONAL THERAPY: Patients also receive conventional therapy comprising methylprednisolone sodium succinate IV every 12 hours on for 7-14 days beginning on day 1 and budesonide PO on days 1-56. Patients with response by day 7-14 may begin taper and receive methylprednisolone PO on days 28-56. Treatment continues in the absence of disease progression or unacceptable toxicity. IST: Patients receive conventional IST or continue their previous prophylactic regimen beginning on day 1 to 56 (or beyond) at the discretion of the treating physician.

Primary Outcome Measures

Name	Time	Method
Incidence of discontinuation of systemic GCs without acute GvHD flare and without disease progression/recurrence	By day 360
Proportions of response among surviving patients	Day 28
Rate of acute (and/or chronic) GvHD-free survival	Day 56	Simon's two-stage design will be used. The null hypothesis that the true CR rate is 30% will be tested against a one-sided alternative and presented with a 95% confidence interval.
Proportions of progression among surviving patients	Day 28

Secondary Outcome Measures

Name	Time	Method
Daily and cumulative GC dose	Day 28	Descriptive measures will be provided at each time point specified.
Incidence of opportunistic infections	Day 180	Descriptive measures will be provided at each time point specified.
NRM	Day 360	Descriptive measures will be provided at each time point specified.
GvHD-free survival	Day 360	Descriptive measures will be provided at each time point specified. Survival estimates will be calculated using Kaplan-Meier estimation.
Feasibility	Up to day 360	Feasibility will be defined as less than three IASA sessions for any reason and obvious procedure-related problems in \>= 10% of patients. Descriptive measures will be provided at each time point specified.
Incidence of acute GvHD "flare" after CR/PR requiring modification and/or additional agents (and/or 2.5 mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) for systemic therapy	Up to day 56	Descriptive measures will be provided at each time point specified.
Incidence of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 toxicities	Up to day 360	Frequencies of toxicities grade 2 or higher will be totaled at the conclusion of the study.
Non-relapse mortality (NRM)	Day 180	Descriptive measures will be provided at each time point specified.
Incidence of chronic GvHD	By day 360	Descriptive measures will be provided at each time point specified.
Overall survival	Day 360	Descriptive measures will be provided at each time point specified. Survival estimates will be calculated using Kaplan-Meier estimation.

Trial Locations

Locations (1)

Comprehensive Cancer Center of Wake Forest University; 🇺🇸 Winston-Salem, North Carolina, United States