Sirolimus as Secondary Therapy in Chronic Graft-Versus-Host Disease Not Responding To Prior Treatment

A Phase II Clinical Trial to Evaluate the Safety and Efficacy of Sirolimus for Secondary Treatment of Chronic Graft-versus-Host Disease

This phase II trial studies the side effects and how well sirolimus works as secondary therapy in treating patients with chronic graft-versus-host disease (GVHD) that did not respond to prior treatment. Sirolimus may be an effective treatment for chronic GVHD

Study Overview

• Status: Completed
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Drug: sirolimus

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the safety of sirolimus administered at a dose which provides steady-state, whole blood trough levels of 5-10 ng/mL in patients with chronic GVHD.

II. To determine whether administration of sirolimus provides benefit for patients with chronic GVHD that has not responded adequately to previous systemic treatment.

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD). Patients continue to receive prednisone and cyclosporine or tacrolimus at the discretion of the managing physician.

After completion of study treatment, patients are followed up periodically.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Biopsy-confirmed diagnosis of clinical extensive chronic GVHD with inadequate response to previous treatment and where secondary systemic therapy is indicated because of

  • Clinical progression of signs and symptoms of chronic GVHD in a previously involved organ, or
  • Development of signs and symptoms of chronic GVHD in a previously uninvolved organ, or
  • Absence of improvement after 3 months of primary treatment, or
  • Continued need for treatment with prednisone at doses >= 1.0 mg/kg/day for more than 2 months, without qualification for type of donor, graft or conditioning regimen
• Patient or guardian able and willing to provide informed consent
• Stated willingness to use contraception in women of child-bearing potential (Food and Drug Administration [FDA] requirement)
• Stated willingness of the patient to comply with study procedures and reporting requirements
• Stated willingness of the physician most involved in management of chronic GVHD (the "managing physician,") to comply with study procedures and reporting requirements

Exclusion Criteria:

• Fungal or viral infection with no radiographic evidence of improvement during continued appropriate antimicrobial therapy
• Cytomegalovirus (CMV) antigenemia unresponsive to antiviral therapy
• Active disseminated varicella zoster virus (VZV) infection with persistent non-crusted lesions
• Inability to tolerate oral medications
• Absolute neutrophil count (ANC) < 1500/uL
• Platelet count < 50,000/uL
• Persistent or recurrent malignancy, including histopathologic evidence of myeloma or lymphoma; patients with breakpoint cluster region-abelson (bcr/abl) detected by polymerase chain reaction (PCR) assay as the only evidence of persistent chronic myeloid leukemia may be enrolled
• Pregnancy
• Known history of hypersensitivity to sirolimus

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sirolimus; Study participants receive sirolimus added once daily to their baseline combination therapy of prednisone plus either cyclosporine or tacrolimus at the discretion of the managing physician. Treatment other than cyclosporine (or tacrolimus) and prednisone must be discontinued when administration of sirolimus is started. Topical therapy, including psoralen and UVA irradiation (PUVA), glucocorticoid creams, topical tacrolimus, oral beclomethasone, topical azathioprine and ophthalmic glucocorticoids may be given at the discretion of the managing physician in consultation with the transplant center.

Drug: sirolimus; Given PO; Other Names: Rapamune; AY 22989; rapamycin; SLM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Treatment Success	Defined as the absence of any immunosuppressive treatment, including sirolimus, with resolution of all reversible manifestations of chronic GVHD and no additional systemic therapy.	Approximately 7 years
Number of Participants Experiencing Treatment Failure	Defined as the initiation of additional systemic therapy, development of bronchiolitis obliterans, or death from causes other than recurrent malignancy during primary treatment for chronic GVHD, whichever occurs first.	Approximately 7 years
Number of Participants Needing Additional Systemic Therapy	Includes any intervention intended to control chronic GVHD through an immunosuppressive effect from oral or parenteral administration of any systemic medication not originally given under auspices of this protocol.	Approximately 7 years
Number of Participants With Recurrent Malignancy	Defined as clinical or histopathologic evidence demonstrating the presence of any malignancy considered as the indication for transplant. Recurrent malignancy will also be defined as any post-transplant intervention not routinely used to prevent the development of overt recurrence, prompted by laboratory evidence of persisting malignant cells but without clinical or histopathologic evidence of recurrence.	Approximately 7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Who Discontinue Administration of Sirolimus Because of Toxicity		Approximately 7 years
Proportion With Infections Categorized by Organism		Approximately 7 years
Secondary Malignancies	Proportion of participants who developed at least one secondary malignancy by 7 years	Up to 7 years
Duration of Treatment With Prednisone		Approximately 7 years
Probability of Survival Without Recurrent Malignancy	Kaplan-Meier estimate assessed at 7 years for probability of survival without recurrent malignancy.	Approximately 7 years
Probability of Overall Survival	Kaplan-Meier estimate assessed at 7 years	Approximately 7 years
Probability of Cumulative Incidence of Death Without Recurrent Malignancy	Analyzed with recurrent malignancy as a competing risk factor. Assessed at 7 years.	Approximately 7 years
Probability of Cumulative Incidence of Recurrent Malignancy	Analyzed with death as a competing risk factor. Assessed at 7 years.	Approximately 7 years

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): June 10, 2010

Study Registration Dates

• First Submitted: March 8, 2004
• First Submitted That Met QC Criteria: March 9, 2004
• First Posted (Estimate): March 10, 2004

Study Record Updates

• Last Update Posted (Actual): June 20, 2017
• Last Update Submitted That Met QC Criteria: May 23, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 1706.00; NCI-2011-01817 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO