Clinical trial NCT04934670: A Study to Compare T-Guard vs Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-vs-Host Disease (BMT CTN 2002)
Official title: A Phase 3, Randomized, Open-Label, Multicenter Study, to Compare T-Guard to Ruxolitinib for the Treatment of Patients With Grade III or IV Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Steroid-Refractory Acute Graft Versus Host Disease
Keywords: T-Guard
Ruxolitinib
Steroid-Refractory
GVHD
Acute GVHD
aGVHD
Grade III
Grade IV
Complete Response (CR)
Transplant
Hematopoietic Stem Cell Transplant (HSCT)
Lead sponsor: Xenikos
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
First posted: 2021-06-22
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized at a ratio of 1:1 between the treatment arms
Primary purpose: TREATMENT

Brief summary: This is an open-label, randomized, Phase 3, multicenter trial, which has been designed to compare the efficacy and safety of T-Guard to ruxolitinib in patients with Grade III or IV Steroid-Refractory acute Graft-Versus-Host Disease (SR-aGVHD). The primary hypothesis is that T-Guard treatment will improve the Day 28 complete response (CR) rate in patients with Grades III and IV SR-aGVHD compared to ruxolitinib.

Detailed description: Graft-vs-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. Acute GVHD (aGVHD) typically develops within the first three months after HSCT and is typically treated with steroid therapy. A significant fraction of the aGVHD population (10-50%) fail to respond to treatment and are deemed steroid-refractory (SR).

Participants that develop Grade III or IV SR aGVHD will be randomized to receive T-Guard or ruxolitinib and will be followed for approximately 180 days. Participants will be stratified by center region (US vs. Europe) and age group (at least 55 years vs. under 55). Participants randomized to the T-Guard arm will receive 4 doses administered intravenously as four 4-hour infusions, and participants randomized to the ruxolitinib arm will receive one dose administered orally twice a day. The primary analysis will include all participants that are randomized.

Eligibility criteria: Inclusion Criteria:

To be eligible to participate in this study, patients must meet the following:

1. Patients must be at least 18.0 years of age at the time of consent.
2. Patient has undergone first allo-HSCT from any donor source or graft source. Recipients of nonmyeloablative, reduced intensity, and myeloablative conditioning regimens are eligible.
3. Patients diagnosed with Grade III/IV SR-aGVHD after allo-HSCT. SR includes aGVHD initially treated at a lower steroid dose, but must meet one of the following criteria:

   * Progressed or new organ involvement after 3 days of treatment with methylprednisolone (or equivalent) of greater than or equal to 2 mg/kg/day
   * No improvement after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day
   * Patients with visceral (GI and/or liver) plus skin aGVHD at methylprednisolone (or equivalent) initiation with improvement in skin GVHD without any improvement in visceral GVHD after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day
   * Patients who have skin GVHD alone and develop visceral aGVHD during treatment with methylprednisolone (or equivalent) of greater than or equal to 1mg/kg/day and do not improve after 3 days of greater than or equal to 2mg/kg/day Improvement or progression in organs is determined by comparing current organ staging to staging at initiation of methylprednisolone (or equivalent) treatment.
4. Patients must have evidence of myeloid engraftment (e.g., absolute neutrophil count greater than or equal to 0.5 × 109/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed.
5. Patients or an impartial witness (in case the patient is capable of providing verbal consent but not capable of signing the informed consent form (ICF)) should have given written informed consent.

Exclusion Criteria:

Patients will be excluded from study entry if they meet any of the following exclusion criteria:

1. Patients who have a creatinine greater than or equal to 2mg/dL or estimated creatinine clearance less than 40 mL/min or those requiring hemodialysis.
2. Patients who have been diagnosed with active thrombotic microangiopathy (TMA), defined as meeting all the following criteria:

   * Greater than 4% schistocytes in blood (or equivalent if semiquantitative scale is used e.g., 3+ or 4+ schistocytes on peripheral blood smear)
   * De novo, prolonged or progressive thrombocytopenia (platelet count less than 50 x 109/L or 50% or greater reduction from previous counts)
   * Sudden and persistent increase in lactate dehydrogenase concentration greater than 2x the upper level of normal (ULN)
   * Decrease in hemoglobin concentration or increased transfusion requirement attributed to Coombs-negative hemolysis
   * Decrease in serum haptoglobin
3. Patients who have previously received treatment with eculizumab.
4. Patients who have previously received checkpoint inhibitors (either before or after allo-HCT).
5. Patients who have been diagnosed with overlap syndrome, that is, with any concurrent features of cGVHD.
6. Patients requiring mechanical ventilation or vasopressor support.
7. Patients who have received any systemic treatment, besides steroids, as upfront treatment of aGVHD or as treatment for SR-aGVHD. Reinstitution of previously used GVHD prophylaxis agents (e.g., tacrolimus, cyclosporin, methotrexate \[MTX\], MMF) or substitutes in cases with previously documented intolerance will be permitted. Previous treatment with a janus kinase (JAK) inhibitor as part of GVHD prophylaxis or treatment is not allowed.
8. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl.
9. Patients who have a creatine kinase (CK) level of greater than 5 times the upper limit of normal.
10. Patients with uncontrolled infections. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Progression of infection is defined as:

    * hemodynamic instability attributable to sepsis OR
    * new symptoms attributable to infection OR
    * worsening physical signs attributable to infection OR
    * worsening radiographic findings attributable to infection Patients with radiographic findings attributable to infection within 4 weeks prior to enrollment must have a repeat radiographic exam within one week of enrollment that documents absence of worsening.
11. Patients with evidence of relapsed, progressing, or persistent malignancy, or who have been treated for relapse after transplant, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
12. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune suppression.
13. Patients with unresolved serious toxicity or complications (other than aGVHD) due to previous transplant.
14. History of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD).
15. Patients with known hypersensitivity to any of the components murine monoclonal antibodies (mAb) or Recombinant Ricin Toxin A-chain (RTA).
16. Patients who have had treatment with any other investigational agent, device, or procedure within 21 days (or 5 half-lives, whichever is greater) prior to enrollment. An investigational agent is defined as medications without any known FDA or European Medicines Agency (EMA) approved indications.
17. Patients who have received more than one allo-HSCT.
18. Patients with known human immunodeficiency virus infection.
19. Patients who have a BMI greater than or equal to 35 kg/m2.
20. Patients who are taking sirolimus must discontinue prior to starting study treatment.

    The sirolimus blood level must be less than 2 ng/mL prior to starting study treatment.
21. Female patients who are pregnant, breast feeding, or, if sexually active and of childbearing potential, unwilling to use effective birth control from start of treatment until 30 days after the last study treatment.
22. Male patients who are, if sexually active and with a female partner of childbearing potential, unwilling to use effective birth control from start of treatment until 65 days after the last study treatment.
23. Patients with any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the patient; or interfere with interpretation of study data.
24. Patients whose decision to participate might be unduly influenced by perceived expectation of gain or harm by participation, such as patients in detention due to official or legal order.

Primary outcomes:
measure: Complete Response (CR)
timeFrame: Day 28
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Day 180
measure: Duration of Complete Response (DoCR)
timeFrame: Day 28
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Saint Louis
country: United States
facility: Washington University St. Louis
state: Missouri
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Brussels
country: Belgium
facility: Site BE301
city: Bruxelles
country: Belgium
facility: Site BE300
city: Gent
country: Belgium
facility: Site BE307
city: Leuven
country: Belgium
facility: Site BE305
city: Liège
country: Belgium
facility: Site BE302
city: Yvoir
country: Belgium
facility: Site BE303
city: Zagreb
country: Croatia
facility: Site HR320
city: Angers
country: France
facility: Site FR341
city: Créteil
country: France
facility: Site FR345
city: La Tronche
country: France
facility: Site FR346
city: Lille
country: France
facility: Site FR355
city: Nantes
country: France
facility: SiteFR354
city: Paris
country: France
facility: SiteFR342
city: Paris
country: France
facility: SiteFR348
city: Pierre-Bénite
country: France
facility: Site FR356
city: Saint-Priest-en-Jarez
country: France
facility: Site FR351
city: Toulouse
country: France
facility: Site FR352
city: Dresden
country: Germany
facility: Site DE367
city: Essen
country: Germany
facility: Site DE364
city: Hannover
country: Germany
facility: Site DE371
city: Heidelberg
country: Germany
facility: Site DE368
city: Leipzig
country: Germany
facility: Site DE360
city: Mainz
country: Germany
facility: Site DE362
city: Muenster
country: Germany
facility: Site DE361
city: Milan
country: Italy
facility: Site IT384
city: Groningen
country: Netherlands
facility: Site NL461
city: Maastricht
country: Netherlands
facility: Site NL460
city: Nijmegen
country: Netherlands
facility: Site NL463
city: Barcelona
country: Spain
facility: Site ES447
city: Madrid
country: Spain
facility: Site ES446
city: Salamanca
country: Spain
facility: Site ES442
city: Santander
country: Spain
facility: Site ES451
city: Sevilla
country: Spain
facility: Site ES452
city: Valencia
country: Spain
facility: Site ES453
city: Valencia
country: Spain
facility: Site ES454
city: Cardiff
country: United Kingdom
facility: Site GB483
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD, MS
role: STUDY_DIRECTOR
affiliation: Xenikos, BV
name: Willem Klaasen
role: STUDY_DIRECTOR
References:
citation: Meyers G, Hamadani M, Martens M, Ali H, Chevallier P, Choe H, Harris AC, Holler E, van Hooren E, Klaassen W, Leifer E, van Oosterhout Y, Perez L, Pusic I, Stelljes M, van der Velden W, Ammatuna E, Beauvais D, Cornillon J, Maziarz RT, Schetelig J, Romeril J, MacMillan ML, Levine JE, Socie G. Anti-CD3/CD7 immunoconjugate (T-Guard) for severe, steroid-refractory GVHD: final report of BMT CTN 2002. Bone Marrow Transplant. 2023 Dec;58(12):1416-1418. doi: 10.1038/s41409-023-02110-4. Epub 2023 Sep 25. No abstract available.