Trial Outcomes & Findings for Sirolimus as Secondary Therapy in Chronic Graft-Versus-Host Disease Not Responding To Prior Treatment (NCT NCT00079183)

NCT ID: NCT00079183

Last Updated: 2017-06-20

Results Overview

Defined as the absence of any immunosuppressive treatment, including sirolimus, with resolution of all reversible manifestations of chronic GVHD and no additional systemic therapy.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 44 participants
• Primary outcome timeframe: Approximately 7 years
• Results posted on: 2017-06-20

Participant Flow

Participant milestones

Measure	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.
Overall Study STARTED	44
Overall Study Drop Outs	7
Overall Study COMPLETED	37
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Measure	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.
Overall Study Withdrawal by Subject	4
Overall Study Study medication non-compliance	2
Overall Study Specimen collection non-compliance	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Sirolimus n=44 Participants 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.
Age, Categorical <=18 years	14 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	26 Participants n=5 Participants
Age, Categorical >=65 years	4 Participants n=5 Participants
Age, Continuous	40.55 years n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	42 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants
Race (NIH/OMB) White	39 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	44 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Number of Participants Experiencing Treatment Success

8 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Number of Participants Experiencing Treatment Failure

9 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Sirolimus n=44 Participants 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.
Number of Participants Needing Additional Systemic Therapy No additional therapy (off immunosuppressive Rx)	8 Participants
Number of Participants Needing Additional Systemic Therapy Additional immunosuppressive therapy (IST) added	9 Participants
Number of Participants Needing Additional Systemic Therapy Still on IST but no new IST added	27 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Number of Participants With Recurrent Malignancy

5 Participants

SECONDARY outcome

Timeframe: Approximately 7 years

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Proportion of Patients Who Discontinue Administration of Sirolimus Because of Toxicity

6 Participants

SECONDARY outcome

Timeframe: Approximately 7 years

Outcome measures

Measure	Sirolimus n=44 Participants 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.
Proportion With Infections Categorized by Organism Proportion of pts with at least 1 bacterial inf'n	19 Participants
Proportion With Infections Categorized by Organism Proportion of pts with at least 1 viral inf'n	6 Participants
Proportion With Infections Categorized by Organism Proportion of pts with at least 1 fungal inf'n	4 Participants
Proportion With Infections Categorized by Organism Proportion of pts with culture negative sepsis	1 Participants
Proportion With Infections Categorized by Organism Proportion of pts with at least 1 infection	21 Participants

SECONDARY outcome

Timeframe: Up to 7 years

Proportion of participants who developed at least one secondary malignancy by 7 years

Outcome measures

Measure	Sirolimus n=44 Participants 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.
Secondary Malignancies Proportion with any second malignancy	15 Participants
Secondary Malignancies Proportion with any subsequent skin malignancy	13 Participants
Secondary Malignancies Proportion with subsequent oral malignancy	3 Participants
Secondary Malignancies Prop'n with subsequent prostate adenocarcinoma	1 Participants
Secondary Malignancies Prop'n with subsequent renal cell carcinoma	1 Participants
Secondary Malignancies Proportion with subsequent bladder carcinoma	1 Participants
Secondary Malignancies Prop'n with post-BMT lymphoproliferative disease	1 Participants

SECONDARY outcome

Timeframe: Approximately 7 years

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Duration of Treatment With Prednisone

45 Months Interval 3.0 to 54.0

SECONDARY outcome

Timeframe: Approximately 7 years

Kaplan-Meier estimate assessed at 7 years for probability of survival without recurrent malignancy.

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Probability of Survival Without Recurrent Malignancy

0.54 disease free survival probability Interval 0.41 to 0.71

SECONDARY outcome

Timeframe: Approximately 7 years

Kaplan-Meier estimate assessed at 7 years

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Probability of Overall Survival

0.59 survival probability Interval 0.46 to 0.75

SECONDARY outcome

Timeframe: Approximately 7 years

Analyzed with recurrent malignancy as a competing risk factor. Assessed at 7 years.

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Probability of Cumulative Incidence of Death Without Recurrent Malignancy

0.25 probability Interval 0.13 to 0.39

SECONDARY outcome

Timeframe: Approximately 7 years

Analyzed with death as a competing risk factor. Assessed at 7 years.

Outcome measures

Measure

Sirolimus n=44 Participants 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.

Probability of Cumulative Incidence of Recurrent Malignancy

0.20 probability Interval 0.1 to 0.33

Adverse Events

Sirolimus

Serious events: 22 serious events

Other events: 30 other events

Deaths: 15 deaths

Serious adverse events

Measure	Sirolimus n=44 participants at risk 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.
Cardiac disorders Hospitalized for Congestive Heart Failure	2.3% 1/44 • Number of events 1
Cardiac disorders Hospitalized for Chest Pain	2.3% 1/44 • Number of events 1
Blood and lymphatic system disorders Hospitalized for Deep Vein Thrombosis (DVT)	4.5% 2/44 • Number of events 2
Blood and lymphatic system disorders Hospitalized for Hemolytic-uremic syndrome (HUS)	4.5% 2/44 • Number of events 2
Cardiac disorders Hospitalized for Hypertension	2.3% 1/44 • Number of events 1
Blood and lymphatic system disorders Hospitalized for Thrombotic Thrombocytopenic Purpura(TTP)	2.3% 1/44 • Number of events 1
Blood and lymphatic system disorders Hospitalized for Idiopathic Thrombocytopenic Purpura (ITP)	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for Fever	2.3% 1/44 • Number of events 1
General disorders Hospitalized for Fatigue	2.3% 1/44 • Number of events 1
Nervous system disorders Hospitalized for Dizziness	2.3% 1/44 • Number of events 1
Gastrointestinal disorders Hospitalized for Dehydration	6.8% 3/44 • Number of events 3
Gastrointestinal disorders Hospitalized for Refractory Diarrhea	2.3% 1/44 • Number of events 1
Surgical and medical procedures Hospitalized for GVHD Flare	6.8% 3/44 • Number of events 3
Immune system disorders Hospitalized for Vitamin K Deficiency	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for CMV (Cytomegalovirus Colitis) Enteritis	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for Coag Negative Staph Bacteremia	6.8% 3/44 • Number of events 3
Infections and infestations Hospitalized for Pneumonia	22.7% 10/44 • Number of events 10
Infections and infestations Hospitalized for Enterobacter Bacteremia	6.8% 3/44 • Number of events 3
Infections and infestations Hospitalized for Pseudomonas Aeruginosa Bacteremia	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for Streptococcus Viridans Bacteremia	4.5% 2/44 • Number of events 2
Infections and infestations Hospitalization for Candida Parapsilosis	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for Septic Shock	2.3% 1/44 • Number of events 1
Endocrine disorders Hospitalized for Hyperglycemia	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for Sinusitis	6.8% 3/44 • Number of events 4
Gastrointestinal disorders Hospitalized for Anorexia	2.3% 1/44 • Number of events 1
Ear and labyrinth disorders Hospitalized for Otitis Media	2.3% 1/44 • Number of events 1
Renal and urinary disorders Hospitalized for Renal Insufficiency	9.1% 4/44 • Number of events 4
Infections and infestations Hospitalized for C. Difficile	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalized for Parainfluenza	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for Respiratory Syncytial Virus	4.5% 2/44 • Number of events 2
Infections and infestations Hospitalization for Chicken Pox	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for Staphylococcus aureus	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for CMV Mucositis	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for Haemophilus influenzae	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for Staphylococcus epidermidis	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for Micrococcus bacteremia	2.3% 1/44 • Number of events 1
Infections and infestations Hospitalization for Staphylococcus Hickman Site Infection	2.3% 1/44 • Number of events 1
Musculoskeletal and connective tissue disorders Hospitalization for Hip Replacement	2.3% 1/44 • Number of events 2
Respiratory, thoracic and mediastinal disorders Hospitalized for Chylothorax	2.3% 1/44 • Number of events 1
Renal and urinary disorders Hospitalized for Oliguric Failure	2.3% 1/44 • Number of events 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hospitalized for tumor in back (relapse)	2.3% 1/44 • Number of events 1
Blood and lymphatic system disorders Hospitalized for Pancytopenia	2.3% 1/44 • Number of events 1

Other adverse events

Measure	Sirolimus n=44 participants at risk 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.
Blood and lymphatic system disorders Neutropenia	9.1% 4/44 • Number of events 6
Blood and lymphatic system disorders Anemia	4.5% 2/44 • Number of events 2
Blood and lymphatic system disorders Thrombocytopenia	9.1% 4/44 • Number of events 4
Cardiac disorders Hypertension	9.1% 4/44 • Number of events 4
General disorders Fatigue	2.3% 1/44 • Number of events 1
Endocrine disorders Diabetic Foot Ulcers	2.3% 1/44 • Number of events 1
Gastrointestinal disorders Diarrhea	11.4% 5/44 • Number of events 6
Gastrointestinal disorders Nausea	6.8% 3/44 • Number of events 3
Gastrointestinal disorders Vomiting	6.8% 3/44 • Number of events 3
Infections and infestations Bronchitis	6.8% 3/44 • Number of events 3
Infections and infestations Pneumonia	4.5% 2/44 • Number of events 3
Infections and infestations C. Difficile	4.5% 2/44 • Number of events 3
Infections and infestations Shingles	2.3% 1/44 • Number of events 1
Infections and infestations sinusitis	11.4% 5/44 • Number of events 5
Infections and infestations Otitis Media	4.5% 2/44 • Number of events 3
Infections and infestations Chicken Pox	2.3% 1/44 • Number of events 1
Infections and infestations Strep Throat	4.5% 2/44 • Number of events 2
Eye disorders Eye Infection	4.5% 2/44 • Number of events 2
Infections and infestations Coag Negative Staph	2.3% 1/44 • Number of events 1
Infections and infestations Left Parotid Gland Infection	2.3% 1/44 • Number of events 1
Infections and infestations Pseudomonas aeruginosa	2.3% 1/44 • Number of events 1
Infections and infestations Aspergillus	2.3% 1/44 • Number of events 1
Infections and infestations BK Virus	2.3% 1/44 • Number of events 1
Skin and subcutaneous tissue disorders Lower Extremity Edema	27.3% 12/44 • Number of events 12
Metabolism and nutrition disorders Hyperlipidemia	25.0% 11/44 • Number of events 12
Musculoskeletal and connective tissue disorders Osteoporosis	6.8% 3/44 • Number of events 3
Nervous system disorders Depression	9.1% 4/44 • Number of events 4
Renal and urinary disorders Renal Insufficiency	22.7% 10/44 • Number of events 12
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal and Squamous Cell	6.8% 3/44 • Number of events 5
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Urinary Bladder Tumor	2.3% 1/44 • Number of events 1

Additional Information

Dr. Paul A. Carpenter

Fred Hutchinson Cancer Research Center

Phone: (206) 667-5191

Email: pcarpent@fredhutch.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place