Methoxsalen and Extracorporeal Photopheresis (ECP) for the Treatment of Pediatric Patients With Steroid Refractory Acute Graft Versus Host Disease

• ClinicalTrials.gov Identifier: NCT02524847
• Recruitment Status: Completed
• First Posted: August 17, 2015
• Last Update Posted: October 30, 2019
• Sponsor: Mallinckrodt
• Information provided by (Responsible Party): Mallinckrodt

Study Description

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 patients with steroid-refractory aGvHD. The study is composed of Screening, Treatment, and Follow-up Periods.

Condition or disease	Intervention/treatment	Phase
Steroid Refractory Acute Graft Versus Host Disease	Drug: Methoxsalen with ECP	Phase 3

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 patient, 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 patients entering the Treatment Period.

Treatment Period:

Once eligibility is established, patients 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.

Patients will be allowed to continue standard aGvHD prophylaxis regimens (e.g., cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil) without the addition of new therapies. Patients 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 patients 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, patients 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. Patient survival will be assessed by passive follow-up (chart review) 26 weeks after initiation of ECP treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: January 20, 2016
• Actual Primary Completion Date: July 16, 2019
• Actual Study Completion Date: July 16, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Methoxsalen with ECP; All patients will receive methoxsalen and ECP, as part of the same interventional treatment for 12 weeks. Treatments will be given 3 times a week for Weeks 1-4 and 2 times a week for Weeks 5-12.	Drug: Methoxsalen with ECP; Combination product: Methoxsalen sterile solution in conjunction with extracorporeal photopheresis (ECP); Other Names: UVADEX®; THERAKOS® CELLEX® Photopheresis System

Outcome Measures

Primary Outcome Measures :

1. Complete response plus partial response (CR+PR) [ Time Frame: 4 weeks ]
   The proportion of patient who achieve an overall response (CR+PR) after 4 weeks of ECP treatment

Secondary Outcome Measures :

1. Safety parameters (vital signs, laboratory tests, and spontaneously reported adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 12 weeks ]
   Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and SAEs
2. Overall response [ Time Frame: 8 weeks ]
   Proportion of patients who achieve an overall response 8 weeks after initiation of ECP treatment
3. Duration of response [ Time Frame: 16 weeks ]
   Duration of response, defined as the length of time a patient maintains a response through Week 16 of the follow-up period
4. Overall response of Glucksberg criteria [ Time Frame: 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) ]
   Proportion of patients who achieve an overall response after 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) of ECP treatment according to the modified Glucksberg Criteria
5. Steroid sparing effect [ Time Frame: 12 weeks ]
   Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks after initiation of ECP treatment
6. Organ specific CR+PR rates [ Time Frame: 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) ]
   Organ specific CR+PR rates at 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) after initiation of ECP treatment

Other Outcome Measures:

1. Very good partial response (VGPR) [ Time Frame: 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) ]
   Proportion of patients who achieve a VGPR 4 weeks (Day 28), 8 weeks (Day 56), and 12 weeks (Day 84) after initiation of ECP treatment
2. Additional immunosuppressive therapy [ Time Frame: 12 weeks ]
   Addition of use of alternative immunosuppressive therapies throughout the 12 week Treatment Period
3. Nonrelapse mortality [ Time Frame: 12 weeks (Day 84) and 16 weeks (Day 112) ]
   Nonrelapse mortality 12 weeks (Day 84) and 16 weeks (Day 112) after initiation of ECP treatment
4. Performance status [ Time Frame: 4 weeks (Day 28) and 8 weeks (Day 56) ]
   Performance status (Karnofsky/Lansky score) 4 weeks (Day 28) and 8 weeks (Day 56) after initiation of ECP treatment

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 12 mg/kg/day methylprednisolone or equivalent in subjects with lower 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 subjects with disease confined to upper GI disease or lesser degrees of skin GvHD.
   • Subjects 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/L.
   • Creatinine level < 2 times the upper limit of normal.
5. For patients with isolated upper GI symptoms, pre-Screening biopsy results to confirm diagnosis of aGvHD.

6. Female patients 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 patients 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. Patient 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 mm3.
20. Currently being treated with any systemic immunosuppressive or biologic therapy for the treatment of a medical condition other than aGvHD.
21. Female patient is breastfeeding or pregnant.
22. Any medical concerns that may pose risk to the patient.
23. Any psychological, familial, sociological, and/or geographical condition that may potentially hamper compliance with the study protocol and follow-up schedule.

Contacts and Locations

  Show 32 Study Locations

Sponsors and Collaborators

Mallinckrodt

Investigators

• Principal Investigator: Carrie Kitko, MD; Vanderbilt Medical Center

More Information

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT02524847 History of Changes
• Other Study ID Numbers: TKS-2014-001
• First Posted: August 17, 2015
• Last Update Posted: October 30, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases; Methoxsalen; Photosensitizing Agents; Dermatologic Agents