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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00079183

Enrollment

Registered

2004-03-10

Start date

2002-04-30

Completion date

2010-06-10

Last updated

2017-06-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Graft Versus Host Disease

Brief summary

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

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.

Interventions

DRUGsirolimus

Given PO

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

SUPPORTIVE_CARE

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Experiencing Treatment Success	Approximately 7 years	Defined as the absence of any immunosuppressive treatment, including sirolimus, with resolution of all reversible manifestations of chronic GVHD and no additional systemic therapy.
Number of Participants Experiencing Treatment Failure	Approximately 7 years	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.
Number of Participants Needing Additional Systemic Therapy	Approximately 7 years	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.
Number of Participants With Recurrent Malignancy	Approximately 7 years	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.

Secondary

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	44
Total	44

Arm

Count

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.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Specimen collection non-compliance	1
Overall Study	Study medication non-compliance	2
Overall Study	Withdrawal by Subject	4

Baseline characteristics

Characteristic	Sirolimus
Age, Categorical <=18 years	14 Participants
Age, Categorical >=65 years	4 Participants
Age, Categorical Between 18 and 65 years	26 Participants
Age, Continuous	40.55 years
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	42 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	39 Participants
Region of Enrollment United States	44 Participants
Sex: Female, Male Female	18 Participants
Sex: Female, Male Male	26 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	15 / 44
other Total, other adverse events	30 / 44
serious Total, serious adverse events	22 / 44

Outcome results

Primary

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.