Steroid Refractory Acute Graft Versus Host Disease
Conditions
Brief summary
This is a single-arm, open-label, multicenter study of the efficacy of UVADEX® (methoxsalen) Sterile Solution in conjunction with THERAKOS® CELLEX® Photopheresis Systems (ECP) in pediatric participants with steroid-refractory aGvHD. The study is composed of Screening, Treatment, and Follow-up Periods.
Detailed description
Screening: After the informed consent/assent form (ICF) is signed, the screening assessments will be performed in a single visit to establish the eligibility of the participant, based on inclusion and exclusion criteria, as well as aGvHD grading. Scheduling of the first week of ECP treatments and the arrangements for availability of typed and cross-matched donor packed red blood cells (PRBCs) for transfusion, if required, will be made in advance of participants entering the Treatment Period. Treatment Period: Once eligibility is established, participants will enter the 12-week ECP Treatment Period. The availability of typed and cross-matched donor PRBCs for transfusion during treatment, if needed, should be established prior to the scheduling of ECP treatments. Participants will be allowed to continue standard aGvHD prophylaxis regimens (e.g., cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil) without the addition of new therapies. Participants will be allowed to discontinue prophylaxis regimens for reasons of toxicity, and will also be allowed to switch to another prophylaxis medication within the same class (e.g., the calcineurin inhibitors cyclosporine and tacrolimus) for reasons of toxicity. All participants enrolled in this trial will have received corticosteroids for the treatment of aGvHD. After entering the treatment period on study, tapering of steroids by total weekly decrements of 12.5% to 25% of the steroid dose at initiation of ECP therapy is permitted after a sustained response of aGvHD has been observed for at least 3 consecutive days, with the suggested goal to decrease the starting steroid dose by at least 50% 4 weeks after initiation of ECP. Follow-Up Period: After completion of the 12-week Treatment Period, participants may continue ECP treatment on commercial product at the Principal Investigator's discretion. Acute GvHD status will be assessed 4 weeks after completion of the Treatment Period. Participant survival will be assessed by passive follow-up (chart review) 26 weeks after initiation of ECP treatment.
Interventions
DRUGMethoxsalen
Sterile solution used in conjunction with photopheresis procedure.
PROCEDUREExtracorporeal Photopheresis (ECP)
Sponsors
Therakos, Inc., a Mallinckrodt Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: 1. Male or female 1 to 21 years of age at the time of consent 2. Steroid-refractory grade B-D aGvHD. * Steroid-refractory is defined as a failure to respond to steroid treatment, with failure to respond defined as any grade B-D (IBMTR grading) aGvHD that shows progression ≥ 3 days, or no improvement by 5 days of treatment with 2 mg/kg/day methylprednisolone or equivalent in participants with lower gastrointestinal (GI) or liver disease, or skin disease associated with bullae. Grade D organ involvement will be limited to skin and liver. * Steroid refractory may also be defined as a failure to respond to 1 mg/kg/day of methylprednisolone or equivalent in participants with disease confined to upper GI disease or lesser degrees of skin GvHD * Participants with lack of complete response after 2 weeks of steroid treatment 3. A Lansky scale Performance Status score ≥ 30 4. Laboratory values are within the following limits, assessed within 3 days of the first study treatment: * Absolute neutrophil count \> 0.5 × 10\^9/liter (L) * Creatinine level \< 2 times the upper limit of normal 5. For participants with isolated upper GI symptoms, pre-Screening biopsy results to confirm diagnosis of aGvHD 6. Female participants of childbearing potential and nonsterilized males who are sexually active with a female partner must be practicing highly effective, reliable, and medically approved contraceptive regimen throughout their participation in the study and for 3 months following the last ECP treatment. Or, for the US only, abstinence may be used in place of an approved contraceptive regimen. Females of childbearing potential are those who have reached the onset of menarche, or 8 years of age, whichever comes first. Approved contraceptive methods for female participants of childbearing potential or nonsterilized males who are sexually active with a female partner are as follows: * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository * Established use of oral, injectable, or implanted hormonal methods of contraception. * Placement of an intrauterine device or intrauterine system 7. Signed informed consent/assent is obtained before conducting any study procedures; the parent, legal guardian, or legally authorized representative of a minor must also provide written informed consent Exclusion: 1. Currently enrolled in another clinical trial for the treatment of aGvHD 2. Use of any experimental regimens or medication(s) for aGvHD treatment 3. Treatment with \> 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within 30 days prior to the first study treatment 4. Overt signs of relapse of the underlying condition 5. Uncontrolled viral, fungal, or bacterial infection 6. Platelet count \< 20.0 × 10\^9/L, despite platelet transfusion 7. Inability to tolerate the extracorporeal volume shifts associated with ECP treatment 8. Uncontrolled GI bleeding 9. Veno-occlusive liver disease 10. Life expectancy \< 4 weeks 11. Participant requires invasive ventilation or vasopressor support 12. Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection (proof of seronegativity within 6 months of screening is required) 13. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its excipients 14. Known hypersensitivity and allergy to heparin and Anticoagulant Citrate Dextrose Formula-A (ACD-A) 15. Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus, albinism) or aphakia 16. Coagulation disorders that cannot be corrected with simple transfusion 17. Co-existing melanoma, basal cell, or squamous cell skin carcinoma 18. Previous splenectomy 19. White blood cell count greater than 25,000 cubic millimeter (mm\^3) 20. Currently being treated with any systemic immunosuppressive or biologic therapy for the treatment of a medical condition other than aGvHD 21. Female participant is breastfeeding or pregnant 22. Any medical concerns that may pose risk to the participant 23. Any psychological, familial, sociological, and/or geographical condition that may potentially hamper compliance with the study protocol and follow-up schedule
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Overall Response (OR) Using the Modified International Bone Marrow Transplant Registry (IBMTR) Severity Index at Week 4 | 4 weeks | OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows: * CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment * PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 8 | 8 weeks | OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows: * CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment * PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment |
| Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 12 | 12 weeks | OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows: * CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment * PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment |
| Duration of Response (Days) Within 16 Weeks Using Modified IBMTR Severity Index | 16 weeks | Duration of first response is presented for patients whose disease progressed. Duration of response is defined in the following way: Patients whose response failed: Date at which 1st disease progression occurs - date of 1st response +1. Patients whose response did not relapse: Date of 16 week follow-up or final assessment prior to week 16 (if patient withdrew early) - date of 1st response. |
| Number of Participants With Adverse Events | 16 weeks | Clinically significant changes in vital signs, laboratory values and investigations are reported as adverse events. Summary data are provided below, with details listed in the adverse events module. |
| Cumulative Dose of Daily Steroids | From diagnosis of aGvHD to 12 Weeks | Steroids administered from diagnosis of aGvHD to 12 Weeks after initiation of ECP treatment |
| Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | at 4, 8 and 12 weeks | Number of patients whose skin was rated as Stage 0 - 4 using the modified Glucksberg criteria based on the Graft versus Host Disease (GvHD) rash - Stages are defined as 0=No GvHD rash, 1=Maculopapular rash on \<25% body surface area (BSA), 2=Maculopapular rash on 25-50% BSA, 3=Maculopapular rash on \>50% BSA, and 4=Generalized erythroderma plus bullous formation, which are blisters bigger than 5 mm across |
| Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | at 4, 8 and 12 weeks | Number of patients whose liver was rated as Stage 0 - 4 on the modified Glucksberg criteria - Stages are based on level of bilirubin, defined as: Stage 0 = Bilirubin \< 2.0 mg/dL, Stage 1 = Bilirubin 2.0-3.0 mg/dL, Stage 2 = Bilirubin 3.1-6.0 mg/dL, Stage 3 = Bilirubin 6.1-15.0 mg/dL, and Stage 4 = Bilirubin \> 15.0 mg/dL |
| Overall Response Rate (ORR) According to the Modified Glucksberg Criteria | 4 weeks, 8 weeks, and 12 weeks | ORR is defined as the percentage of patients who achieve an overall response after 4 weeks, 8 weeks, and 12 weeks of ECP treatment according to a scoring algorithm applied to calculate the grade of aGvHD using the modified Glucksberg Criteria. |
Countries
Austria, France, Germany, Hungary, Italy, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were recruited by multiple treatment centers in the United States and Europe
Participants by arm
| Arm | Count |
|---|---|
| Methoxsalen With ECP Participants receive methoxsalen 20 µg/ml in conjunction with ECP procedure three times per week for Weeks 1 to 4, and two times per week for Weeks 5 to 12. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Condition no Longer Requires Treatment | 4 |
| Overall Study | Death | 1 |
| Overall Study | Reason not Specified | 1 |
| Overall Study | Unsatisfactory Therapeutic Effect | 4 |
Baseline characteristics
| Characteristic | Methoxsalen With ECP |
|---|---|
| Age, Continuous | 8.6 years STANDARD_DEVIATION 5.02 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized White | 22 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 29 |
| other Total, other adverse events | 17 / 29 |
| serious Total, serious adverse events | 12 / 29 |
Outcome results
Primary
Number of Participants Achieving Overall Response (OR) Using the Modified International Bone Marrow Transplant Registry (IBMTR) Severity Index at Week 4
OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows: * CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment * PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment
Time frame: 4 weeks
Population: All participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methoxsalen With ECP | Number of Participants Achieving Overall Response (OR) Using the Modified International Bone Marrow Transplant Registry (IBMTR) Severity Index at Week 4 | 16 Participants |
p-value: <0.00195% CI: [35.7, 73.6]t-test, 2 sided
Secondary
Cumulative Dose of Daily Steroids
Steroids administered from diagnosis of aGvHD to 12 Weeks after initiation of ECP treatment
Time frame: From diagnosis of aGvHD to 12 Weeks
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Methoxsalen With ECP | Cumulative Dose of Daily Steroids | 1917 mg |
Secondary
Duration of Response (Days) Within 16 Weeks Using Modified IBMTR Severity Index
Duration of first response is presented for patients whose disease progressed. Duration of response is defined in the following way: Patients whose response failed: Date at which 1st disease progression occurs - date of 1st response +1. Patients whose response did not relapse: Date of 16 week follow-up or final assessment prior to week 16 (if patient withdrew early) - date of 1st response.
Time frame: 16 weeks
Population: Population meeting the criterion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Methoxsalen With ECP | Duration of Response (Days) Within 16 Weeks Using Modified IBMTR Severity Index | 13.5 days |
Secondary
Number of Participants With Adverse Events
Clinically significant changes in vital signs, laboratory values and investigations are reported as adverse events. Summary data are provided below, with details listed in the adverse events module.
Time frame: 16 weeks
Population: All participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Methoxsalen With ECP | Number of Participants With Adverse Events | Non-serious TEAE at 5% threshold | 17 Participants |
| Methoxsalen With ECP | Number of Participants With Adverse Events | Any serious AE | 12 Participants |
| Methoxsalen With ECP | Number of Participants With Adverse Events | Death for any cause | 3 Participants |
Secondary
Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria
Number of patients whose liver was rated as Stage 0 - 4 on the modified Glucksberg criteria - Stages are based on level of bilirubin, defined as: Stage 0 = Bilirubin \< 2.0 mg/dL, Stage 1 = Bilirubin 2.0-3.0 mg/dL, Stage 2 = Bilirubin 3.1-6.0 mg/dL, Stage 3 = Bilirubin 6.1-15.0 mg/dL, and Stage 4 = Bilirubin \> 15.0 mg/dL
Time frame: at 4, 8 and 12 weeks
Population: All participants with scores at the given time point
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 0 | 19 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 1 | 1 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 2 | 1 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 3 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 4 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 0 | 13 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 1 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 2 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 3 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 4 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 0 | 12 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 1 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 2 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 3 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 4 | 0 Participants |
Secondary
Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria
Number of patients whose skin was rated as Stage 0 - 4 using the modified Glucksberg criteria based on the Graft versus Host Disease (GvHD) rash - Stages are defined as 0=No GvHD rash, 1=Maculopapular rash on \<25% body surface area (BSA), 2=Maculopapular rash on 25-50% BSA, 3=Maculopapular rash on \>50% BSA, and 4=Generalized erythroderma plus bullous formation, which are blisters bigger than 5 mm across
Time frame: at 4, 8 and 12 weeks
Population: All participants with scores at the given time point
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 0 | 9 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 1 | 8 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 2 | 3 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 3 | 3 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 4 | Stage 4 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 0 | 11 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 1 | 5 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 2 | 1 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 3 | 1 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 8 | Stage 4 | 0 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 0 | 10 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 1 | 2 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 2 | 1 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 3 | 1 Participants |
| Methoxsalen With ECP | Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria | Week 12 | Stage 4 | 0 Participants |
Secondary
Overall Response Rate (ORR) According to the Modified Glucksberg Criteria
ORR is defined as the percentage of patients who achieve an overall response after 4 weeks, 8 weeks, and 12 weeks of ECP treatment according to a scoring algorithm applied to calculate the grade of aGvHD using the modified Glucksberg Criteria.
Time frame: 4 weeks, 8 weeks, and 12 weeks
Population: All participants with a score at the given time point
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methoxsalen With ECP | Overall Response Rate (ORR) According to the Modified Glucksberg Criteria | Week 4 | 50 percentage of participants |
| Methoxsalen With ECP | Overall Response Rate (ORR) According to the Modified Glucksberg Criteria | Week 8 | 63.2 percentage of participants |
| Methoxsalen With ECP | Overall Response Rate (ORR) According to the Modified Glucksberg Criteria | Week 12 | 78.6 percentage of participants |
Secondary
Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 12
OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows: * CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment * PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment
Time frame: 12 weeks
Population: Evaluable Participants (Participants with appropriate efficacy data at the given time point)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methoxsalen With ECP | Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 12 | 78.6 percentage of participants |
Secondary
Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 8
OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows: * CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment * PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment
Time frame: 8 weeks
Population: Evaluable Participants (Participants with appropriate efficacy data at the given time point)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methoxsalen With ECP | Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 8 | 73.7 percentage of participants |