Graft vs Host Disease
Conditions
Brief summary
This study will test the safety and effectiveness CC-4047 (pomalidomide) in patients with advanced, steroid refractory graft-versus-host disease.
Detailed description
Chronic Graft vs. Host Disease is a major complication after allogeneic hematopoietic stem cell transplantation developing in 30 - 70% of patients. It is a multisystem alloimmune and autoimmune disorder with a negative impact on quality of life and functional status, increased need for extended immunosuppression and is the leading cause of late transplant related mortality. CC-4047 is a novel immune modulatory drug that is a thalidomide analog with a 4,000 fold greater inhibition of TNF-α production related to thalidomide. Several features of CC-4047 suggest that this drug may be useful in treating chronic GVHD including in vitro suppression of TNF-α production, increasing Th1 and stimulation of IL-12 and sIL-Rα. This study is an open-label, single-arm, pilot study of efficacy and safety of CC-4047 in patients with advanced chronic GvHD who failed to achieve a response with high-dose corticosteroids or second line systemic immunosuppressive therapy.
Interventions
DRUGCC-4047
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patient must meet all of the following inclusion criteria: * Must be greater than or equal to 18 years of age at the time of consent. * Must be able to adhere to the study visit schedule and other protocol requirements. * Chronic graft versus host disease (GHVD) developing after allogeneic hematological stem cell transplantation diagnosed using NIH criteria for diagnosis and staging of chronic GvHD (including both classic chronic GvHD and overlap syndrome) * Must have moderate or severe chronic GvHD according to Global Staging System for Chronic GvHD or mild chronic GvHD with platelet count less than 100 x 109/L * Must have failed to achieve response to high dose corticosteroid (average 0.5 mg/kg/day prednisone or equivalent for greater than or equal to 8 weeks), or have failed second line systemic immunosuppressive therapy. * If taking corticosteroids at the time of enrollment, must be on stable or tapering schedule without corticosteroid pulses in the preceding 8 weeks. * If taking secondary systemic immunosuppressive therapy at the time of enrolment, must be on stable or tapering schedule in the preceding 4 weeks. * Karnofsky performance score (KPS) greater than or equal to 60%. * Life expectancy greater than or equal to 3 months. * Female of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse for at least 28 days before starting study drug, while participating in the study, and for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal \[birth control pills, injections, or implants\], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods if needed. * FCBP must agree to pregnancy testing and contraceptive counseling every 28 days during the study. FCBP must also refrain from donating blood and/or egg while participating in the study and for at least 28 days after discontinuation from this study * FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10-14 days prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug. * Must agree to abstain from breastfeeding during study participation and for at least 28 days after study drug discontinuation. * Male Subjects must agree to complete abstinence or to use a condom during sexual contact with with a pregnant female or a female of childbearing potential while participating in the study and for at least 90 days following study drug discontinuation even if he has undergone a successful vasectomy * Must agree to counseling about sexual contact and the potential risks of fetal exposure to pomalidomide every 28 days. * Male subjects will be warned that sharing study drug is prohibited * Must agree to abstain from donating blood for at least 28 days following discontinuation of the study drug. * Must agree to abstain from donating semen or sperm during study participation and for at least 90 days after study drug discontinuation. * Must agree that if a pregnancy or a positive pregnancy test does occur in a the partner of a male study subject during study participation, the investigator must be notified immediately * Patients must agree to not share study drug with anyone during participation in the study. * Must understand and voluntarily sign an informed consent form, or must have a legally authorized representative who is able and willing to voluntarily sign an informed consent form on behalf of the patient.
Exclusion criteria
* Pregnant or lactating females. * New immunosuppressive therapy started within the preceding 4 weeks. * Extracorporeal photopheresis within the preceding 3 months. * Hypersensitivity to any immune modulator drug (IMiD™). * Unable to take prophylactic anticoagulation. * Any condition which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. * Acute, persistent, recurrent or late-onset acute GvHD defined by NIH criteria. * Any of the following laboratory values at registration: * absolute neutrophil count (ANC) less than 1.0 x 109/L, * platelets less than 75 x 109/L, or * creatinine clearance less than 50 mL/min (Cockroft-Gault formula). * Uncontrolled infection requiring systemic antibiotics. * Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection. * Known uncontrolled arrhythmias or symptomatic heart disease or left ventricular ejection fraction less than 40% (an ECHO should be performed as clinically indicated) * Recurrence of cancer for which the transplant was done except for presence of minimal residual disease by PCR. * Other cancer less than or equal to 2 years prior study-entry except: * Basal cell carcinoma of the skin, * Squamous cell carcinoma of the skin, * Carcinoma in situ of the cervix, * Carcinoma in situ of the breast, or * Prostate cancer (Tumor, Node, Metastasis \[TNM\] stage T1a or T1b)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response (Complete Response + Partial Response + Other) | 1 year after last dose of CC-4047 | * CR is defined as complete resolution in all of signs and symptoms at all affected organs and tissues * PR is defined as improvement in greater than or equal to 1 organ/tissue with no progression in any other affected organ/tissue * Improvement in chronic GvHD symptoms less than what meets the definition of a PR is defined as other * Progressive disease is defined as failure of therapy to control chronic GvHD despite increasing the dose of primary therapy or adding second line treatments * No response is defined as no change in disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | 30 days after last dose of CC-4047 or until resolution of event | -Toxicities will be graded according to the NCI CTCAE v3.0. |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 02/02/2009 and closed to participant enrollment on 03/29/2011.
Participants by arm
| Arm | Count |
|---|---|
| CC-4047 Arm CC-4047 2 mg orally every day for 1 course (12 weeks or 84 days). Every 28 days of treatment are considered as 1 cycle and every 3 cycles are are considered as 1 course of treatment. A total of 4 courses of treatment are planned (12 months). | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | CC-4047 Arm |
|---|---|
| Age, Continuous | 46 years |
| Chronic graft-versus-host disease onset De novo | 5 participants |
| Chronic graft-versus-host disease onset Progressive | 1 participants |
| Chronic graft-versus-host disease onset Quiescent | 7 participants |
| Donor type Matched related donor | 7 participants |
| Donor type Matched unrelated donor | 6 participants |
| Global chronic graft-versus-host disease score Moderate | 2 participants |
| Global chronic graft-versus-host disease score Severe | 11 participants |
| Karnofsky performance status | 80 scores on a scale |
| Major organ-systems involved Eyes | 10 participants |
| Major organ-systems involved Joint and Fascia | 10 participants |
| Major organ-systems involved Lungs | 8 participants |
| Major organ-systems involved Mouth | 9 participants |
| Major organ-systems involved Skin | 13 participants |
| Number of prior therapies | 4 number of prior therapies |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
| Years post-transplant | 2.5 years |
| Years since chronic graft-versus-host disease | 1.5 years |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 5 / 13 |
Outcome results
Primary
Overall Response (Complete Response + Partial Response + Other)
* CR is defined as complete resolution in all of signs and symptoms at all affected organs and tissues * PR is defined as improvement in greater than or equal to 1 organ/tissue with no progression in any other affected organ/tissue * Improvement in chronic GvHD symptoms less than what meets the definition of a PR is defined as other * Progressive disease is defined as failure of therapy to control chronic GvHD despite increasing the dose of primary therapy or adding second line treatments * No response is defined as no change in disease.
Time frame: 1 year after last dose of CC-4047
Population: 4 participants discontinued treatment before the third cycle because of adverse-effects and were not evaluable
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CC-4047 Arm | Overall Response (Complete Response + Partial Response + Other) | Partial overall response | 7 participants |
| CC-4047 Arm | Overall Response (Complete Response + Partial Response + Other) | No response | 2 participants |
| CC-4047 Arm | Overall Response (Complete Response + Partial Response + Other) | Complete overall response | 0 participants |
| CC-4047 Arm | Overall Response (Complete Response + Partial Response + Other) | Progressive disease | 0 participants |
Secondary
Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation
-Toxicities will be graded according to the NCI CTCAE v3.0.
Time frame: 30 days after last dose of CC-4047 or until resolution of event
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Community-acquired pneumonia | 1 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Respiratory syncytial virus (RSV) pneumonia | 2 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Tremors/shakiness | 4 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Muscle cramps/musculoskeletal pain | 12 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Fatigue/anxiety | 6 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Sensory neuropathy | 4 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Sepsis | 1 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Aseptic meningitis | 1 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Deep vein thrombosis/pulmonary embolism | 1 participants |
| CC-4047 Arm | Safety as Measured by the Most Common Adverse Effects and Reasons for Dose Reductions or Study-discontinuation | Erythematous skin rash | 1 participants |
Post Hoc
Chronic Graft-versus-host Disease Global Score at the Start/End of the Study
* Global scoring of chronic GvHD consists of questions about various organs including skin, genital tract, lungs, liver, and multiple others. The physician scores each organ from 0 to 3. Score 0 means the patient has no symptoms. Score 1 means the patient has mild symptoms. Score 2 means the patient has moderate symptoms. Score 3 means the patient has severe syptoms. * Mild scoring of chronic GvHD is only 1 or 2 organs or site (except the lung). No clinically significant functional impairment (maximum of score 1 in all affected organs or sites) * Moderate scoring of chronic GvHD is at least 1 organ or site with clinically significant but no major disability (maximum score of 2 in any affected organ or site) or 3 or more organs or sites with no clinically significant functional impairment (maximum of 1 in all affected orgnas or sites) * Severe scoring of chronic GvHD is a major disability caused by chronic GvHD (score of 3 in any organ or site) and lung function score \>=2.
Time frame: 1 year after last dose of CC-4047
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CC-4047 Arm | Chronic Graft-versus-host Disease Global Score at the Start/End of the Study | Starting score Severe/Ending score Severe | 11 participants |
| CC-4047 Arm | Chronic Graft-versus-host Disease Global Score at the Start/End of the Study | Starting score Moderate/Ending score Moderate | 2 participants |
Post Hoc
Organ System Response
Time frame: 1 year after last dose of CC-4047
Population: 4 participants discontinued treatment before the third cycle because of adverse-effects and were not evaluable
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CC-4047 Arm | Organ System Response | Skin erythema - complete organ response | 2 participants |
| CC-4047 Arm | Organ System Response | Mouth - partial organ response | 0 participants |
| CC-4047 Arm | Organ System Response | Eyes - complete organ response | 1 participants |
| CC-4047 Arm | Organ System Response | Eyes - partial organ response | 1 participants |
| CC-4047 Arm | Organ System Response | Skin erythema - partial organ response | 3 participants |
| CC-4047 Arm | Organ System Response | Skin movable sclerosis - complete organ response | 0 participants |
| CC-4047 Arm | Organ System Response | Skin movable sclerosis - partial organ response | 1 participants |
| CC-4047 Arm | Organ System Response | Mouth - complete organ response | 2 participants |
| CC-4047 Arm | Organ System Response | Gastrointestinal - complete organ response | 2 participants |
| CC-4047 Arm | Organ System Response | Gastrointestinal - partial organ response | 0 participants |
Post Hoc
Survival Rate of CC-4047 Responders
Time frame: Median follow-up 5.6 years (4.2-5.6 years)
Population: Five participants have died and these were the participants who did not respond or were removed from study prior to cycle 3 due to adverse events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CC-4047 Arm | Survival Rate of CC-4047 Responders | 100 percentage of participants |