Chronic Graft Versus Host Disease
Conditions
Keywords
cGVHD, Velcade, bortezomib
Brief summary
The purpose of this research study is to determine the effectiveness of bortezomib (Velcade) plus prednisone for treating chronic graft versus host disease (cGVHD) and the safety of this drug combination in this patient population. Chronic GVHD is a medical condition that may occur after allogeneic stem cell transplantation. The donor's immune system may recognize the participants body (the host) as foreign and attempt to reject it. Bortezomib has been used in other research studies, and information from those studies suggests that this drug may help to control the abnormal immune responses that underlie cGVHD.
Detailed description
* Each treatment cycle lasts five weeks, during which time participants will come to the clinic to receive bortezomib intravenously once a week for the first 4 weeks. Prednisone will be taken orally on a daily basis and dose reduction may be initiated after 1 cycle of therapy. * During all treatment cycles, participants will have the following: physical exam and blood work. At the end of cycle 3 (week 15) the participants cGVHD will be evaluated. These assessments may include an eye examination, a skin examination, a pulmonary function test and/or, a flexion assessment test. * Participants will receive 3 cycles of bortezomib.
Interventions
DRUGbortezomib
Given intravenously at a dose of 1.3 mg/m\^2 once a week for the first four weeks of a five week cycle for a total of 3 cycles
DRUGPrednisone
Taken orally once a day at a dose of 0.5-1 mg/kg. Dose reduction may be initiated after 1 cycle of therapy. A suggested taper is 10-25% every 1-2 weeks.
Sponsors
Millennium Pharmaceuticals, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Recipients of allogeneic stem cell transplantation with myeloablative or non-myeloablative conditioning regimens * 100 days or more past stem cell transplantation * Recipients of matched or mismatched, related or unrelated adult donor stem cells * Must have cGVHD requiring systemic therapy * No addition or subtraction of other immunosuppressive medications. The dose of immunosuppressive medicines may be adjusted based on the therapeutic range of that drug. However, if cGVHD occurs during a taper of immune suppression, the medication(s) may not be increased back up to therapeutic level, but will continue a the taper dose for the 15 week study duration * Adequate bone marrow, hepatic and renal function as outlined in the protocol * Does not require hemodialysis * 18 years of age or older * ECOG Performance Status of 0-2 or Karnofsky performance score of 70% or greater * Life expectancy of more than 3 months
Exclusion criteria
* Systemic steroid therapy in the 4 weeks prior to enrollment * Active malignant disease after transplantation. Complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy will not be considered in this category * Active uncontrolled infection * Peripheral neuropathy CTC Grade 1 (or greater) with pain in the 4 weeks before enrollment. Other neurological deficits must be reviewed with the study PI prior to study entry * Myocardial infarction within 6 months prior to enrollment or has NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities * Hypersensitivity to bortezomib, boron, or mannitol * Female subject is pregnant or breast-feeding * Serious medical or psychiatric illness likely to interfere with participation in this clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Patients had their cGVHD assessed at Baseline and at 15 weeks or end of therapy | Participants had their cGVHD evaluated per NIH consensus criteria: Complete response: resolution of all reversible manifestations of cGVHD. Partial response: a decrease ≥ 1 point on a 3-point organ-specific scale or 2 points or more on a 10-point global scale without progression in any organ sites. Stable disease: no evidence of cGVHD response without evidence of progressive cGVHD. Progressive cGVHD: increase of ≥ 1 point on an organ-specific 3-point scale, addition of a new immunosuppressive agent prior to the completion of 15 weeks of combination therapy, or requirement an increase in the total daily dose of corticosteroids above a participant's baseline corticosteroid dose during the 15-week combined treatment period. Mixed response: a response in primary sites of cGVHD involvement but interval progressive cGVHD in other organs or sites. Responses were not scored for oral or ocular cGVHD, since topical therapies were permitted during the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Tolerating >50% Steroid Dose Reduction After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | After 15 weeks of bortezomib plus prednisone therapy | The participants' total daily steroid dose was recorded at baseline and after a 15 week course of treatment. Starting at a dose of 0.5-1 mg/kg, dose reduction of steroids was permitted after 1 cycle of therapy. The suggested taper was 10-25% every 1-2 weeks. . |
| The Toxicity of a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Toxicities were collected from the start of treatment through 15 weeks of therapy or end of study treatmetn | Participants' toxicities were graded based on the CTCAE version 3.0. The toxicities were then given an attribution to the velcade treatment: unrelated, unlikely, possible, probable, definite. |
| Proportion of cGVHD Patients Requiring Prednisone by 1 Year After Therapy | 1 year after the start of study treatment | Participants who were still being followed 1 year after the start of therapy had their prednisone dose recorded. |
| Overall and cGVHD Progression-free Survival by 1 Year After Therapy | 2 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Velcade (Bortezomib) Prednisone : Taken orally once a day at a dose of 0.5-1 mg/kg. Dose reduction may be initiated after 1 cycle of therapy. A suggested taper is 10-25% every 1-2 weeks.
Bortezomib : Given intravenously at a dose of 1.3 mg/m\^2 once a week for the first four weeks of a five week cycle for a total of 3 cycles | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | AML Relapse | 1 |
| Overall Study | Lack of Efficacy | 2 |
| Overall Study | Unrelated Fungal Infection | 1 |
Baseline characteristics
| Characteristic | Velcade (Bortezomib) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 51 years |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 22 |
| serious Total, serious adverse events | 2 / 22 |
Outcome results
Primary
Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD
Participants had their cGVHD evaluated per NIH consensus criteria: Complete response: resolution of all reversible manifestations of cGVHD. Partial response: a decrease ≥ 1 point on a 3-point organ-specific scale or 2 points or more on a 10-point global scale without progression in any organ sites. Stable disease: no evidence of cGVHD response without evidence of progressive cGVHD. Progressive cGVHD: increase of ≥ 1 point on an organ-specific 3-point scale, addition of a new immunosuppressive agent prior to the completion of 15 weeks of combination therapy, or requirement an increase in the total daily dose of corticosteroids above a participant's baseline corticosteroid dose during the 15-week combined treatment period. Mixed response: a response in primary sites of cGVHD involvement but interval progressive cGVHD in other organs or sites. Responses were not scored for oral or ocular cGVHD, since topical therapies were permitted during the study.
Time frame: Patients had their cGVHD assessed at Baseline and at 15 weeks or end of therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Velcade (Bortezomib) | Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with a complete response in cGVHD | 2 participants |
| Velcade (Bortezomib) | Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with an partial response in cGVHD | 14 participants |
| Velcade (Bortezomib) | Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with stable cGVHD | 1 participants |
| Velcade (Bortezomib) | Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with progressive cGVHD | 2 participants |
| Velcade (Bortezomib) | Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with mixed response | 1 participants |
Secondary
Overall and cGVHD Progression-free Survival by 1 Year After Therapy
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Velcade (Bortezomib) | Overall and cGVHD Progression-free Survival by 1 Year After Therapy | 2-year Cum-incidence of Non-relapse mortality | 14 percentage of participants |
| Velcade (Bortezomib) | Overall and cGVHD Progression-free Survival by 1 Year After Therapy | 2-year Cum-incidence of malignant relapse | 14 percentage of participants |
| Velcade (Bortezomib) | Overall and cGVHD Progression-free Survival by 1 Year After Therapy | 2 year progression-free survival | 73 percentage of participants |
| Velcade (Bortezomib) | Overall and cGVHD Progression-free Survival by 1 Year After Therapy | 2-year Overall survival | 73 percentage of participants |
Secondary
Proportion of cGVHD Patients Requiring Prednisone by 1 Year After Therapy
Participants who were still being followed 1 year after the start of therapy had their prednisone dose recorded.
Time frame: 1 year after the start of study treatment
Population: Participants who were still being followed 1 year after the start of therapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Velcade (Bortezomib) | Proportion of cGVHD Patients Requiring Prednisone by 1 Year After Therapy | Participants still requiring prednisone | 11 participants |
| Velcade (Bortezomib) | Proportion of cGVHD Patients Requiring Prednisone by 1 Year After Therapy | Participants off prednisone | 6 participants |
Secondary
Proportion of Patients Tolerating >50% Steroid Dose Reduction After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD
The participants' total daily steroid dose was recorded at baseline and after a 15 week course of treatment. Starting at a dose of 0.5-1 mg/kg, dose reduction of steroids was permitted after 1 cycle of therapy. The suggested taper was 10-25% every 1-2 weeks. .
Time frame: After 15 weeks of bortezomib plus prednisone therapy
Population: Of the overall 22 patients, 18 patients completed 3 cycles (15 weeks) of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velcade (Bortezomib) | Proportion of Patients Tolerating >50% Steroid Dose Reduction After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | 14 participants |
Secondary
The Toxicity of a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD
Participants' toxicities were graded based on the CTCAE version 3.0. The toxicities were then given an attribution to the velcade treatment: unrelated, unlikely, possible, probable, definite.
Time frame: Toxicities were collected from the start of treatment through 15 weeks of therapy or end of study treatmetn
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Velcade (Bortezomib) | The Toxicity of a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with >= Grade 3, unrelated/unlikely | 7 participants |
| Velcade (Bortezomib) | The Toxicity of a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with >= Grade 3, possible | 1 participants |
| Velcade (Bortezomib) | The Toxicity of a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants with >= Grade 3, probable/definite | 0 participants |