Clinical trial NCT02524847: Methoxsalen and Extracorporeal Photopheresis (ECP) for the Treatment of Pediatric Participants With Steroid Refractory Acute Graft Versus Host Disease
Official title: Single-Arm Study to Assess the Efficacy of UVADEX® (Methoxsalen) Sterile Solution in Conjunction With the THERAKOS® CELLEX® Photopheresis System in Pediatric Patients With Steroid-Refractory Acute Graft-vs-Host Disease (aGvHD)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Steroid Refractory Acute Graft Versus Host Disease
Lead sponsor: Mallinckrodt
Sponsor class: INDUSTRY
First posted: 2015-08-17
Enrollment: 29
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants Achieving Overall Response (OR) Using the Modified International Bone Marrow Transplant Registry (IBMTR) Severity Index at Week 4
timeFrame: 4 weeks
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 16 weeks
measure: Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 8
timeFrame: 8 weeks
measure: Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 12
timeFrame: 12 weeks
measure: Duration of Response (Days) Within 16 Weeks Using Modified IBMTR Severity Index
timeFrame: 16 weeks
measure: Overall Response Rate (ORR) According to the Modified Glucksberg Criteria
timeFrame: 4 weeks, 8 weeks, and 12 weeks
measure: Cumulative Dose of Daily Steroids
timeFrame: From diagnosis of aGvHD to 12 Weeks
measure: Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria
timeFrame: at 4, 8 and 12 weeks
measure: Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria
timeFrame: at 4, 8 and 12 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta, Emory - Children's Center
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Cleveland
country: United States
facility: University Hospitals Rainbow Babies & Children's
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Children's
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Ingram Cancer Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Care Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Wien
country: Austria
facility: St Anna Kinderspital
city: Paris
country: France
facility: Hopital Necker Enfants Malades
city: Paris
country: France
facility: Hôpital universitaire Robert Debré
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Hämatologie und Internistische Onkologie
city: München
country: Germany
facility: Klinikum rechts der Isar, TU München, Klinik- und Poliklinik für Kinder- und Jugendmedizin, Kinderklinik München Schwabing
city: Tübingen
country: Germany
facility: University Hospital Tuebingen
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm, Kinder- und Jugendmedizin
city: Budapest
country: Hungary
facility: United St Istvan and St Laszlo Hospital
city: Padova
country: Italy
facility: U.O.C. Clinica di Oncoematologia Pediatrica Azienda Ospedaliera di Padova
city: Rome
country: Italy
facility: Pediatric Hospital Bambinu Gesu Rome
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Madrid
country: Spain
facility: Hospital Infantil Universitario "Nino Jesus"
city: Salamanca
country: Spain
facility: University Hospital Salamanca
city: Valencia
country: Spain
facility: Hospital LA FE
city: Newcastle
country: United Kingdom
facility: Great North Children's Hospital (RVI)
Study officials:
affiliation: Mallinckrodt
name: Clinical Team Leader
role: STUDY_DIRECTOR
References: