Study of BEGEDINA® vs "Conventional Treatment" for Treating Steroid-Resistant Acute GvHD
Condition: Graft vs Host Disease
MeSH terms: Graft vs Host Disease
Intervention: Begelomab; Conventional Second-line Treatment
Intervention description: BEGEDINA® (Begelomab) is a murine immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and is produced by biotechnological means.; There are no approved second-line treatments for aGvHD and due to the life-threatening nature of the disease it was agreed with the FDA and EMA that BEGEDINA® would be compared with "best conventional second-line treatments" which will be chosen by each center, based on the clinical conditions of the individual subject and according to the standard practice at the study center and which may vary between centers. Treatments are generally biological products and could include anti-thymocyte globulin, monoclonal antibodies, such as anti-CD147, basiliximab, daclizumab and alemtuzumab; mycophenolate mofetil; anti-TNF-alpha; pentostatin; dinileukin diftitox; N-acetyl-cysteine; sirolimus; and visulizumab.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Graft vs Host Disease; Immune System Diseases; Dipeptidyl Peptidase 4; CD4-Positive T-Lymphocytes; Hematopoietic Stem Cell Transplantation

Summary:

      The objectives of this study are to determine the efficacy and safety of BEGEDINA® in
      subjects with steroid resistant acute graft versus host disease (GvHD). GvHD is a rare and
      complex immunological disease occurring in some recipients of allogeneic hematopoietic stem
      cell transplants (HSCTs) and affecting principally the skin, liver and gastrointestinal (GI)
      tissues. The disease is life threatening and may be acute or chronic and the first choice
      treatment for patients with acute GvHD (Grade II or higher) is the immunosuppressive
      corticosteroid hormone methylprednisolone. However, some GvHD patients may be resistant to
      this treatment leading to disease progression and a high rate of morbidity and mortality,
      primarily from infections and/or multi-organ failure. There are currently no other
      satisfactory therapies. BEGEDINA® is a therapeutic monoclonal antibody that recognises and
      binds to CD26 on CD4+ T lymphocytes. BEGEDINA® reduces the activity of CD26 in these cells
      and inhibits the immune response leading to improvement in patients that have shown steroid
      resistance. This study is therefore aimed at demonstrating that BEGEDINA® is a safe and
      effective treatment for steroid-resistant GvHD patients where no other such treatments are
      currently available.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥18 and ≤65 years of age.

          2. Recipient of an allogeneic hematopoietic stem cell transplantation (HSCT). Note:
             Subjects with GvHD following donor lymphocyte infusion post-HSCT are also eligible

          3. Steroid-resistant acute GvHD, Grade II-IV, defined as: progressive disease
             (deterioration of at least 1 stage in 1 organ) after 3 days of primary treatment with
             methylprednisolone 2 mg/kg, or equivalent. or lack of at least a partial response (PR)
             after 7 days of primary treatment with methylprednisolone 2 mg/kg or equivalent. or
             lack of a complete response (CR) after 14 days of primary treatment with
             methylprednisolone 2 mg/kg or equivalent. Note: Subjects who may have received an
             increase in their steroid dose treatment prior to randomization will be eligible for
             enrollment. An increase in steroid dose will not be considered as second-line therapy.

          4. Evidence of previous myeloid engraftment (absolute neutrophil count ≥0.5 x 10^9/L).

          5. Karnofsky Performance Status Scale ≥50%.

          6. Adequate renal function as defined by serum creatinine ≤2 × upper limit of normal or
             calculated creatinine clearance (CrCl) of ≥30 mL/min using the Cockroft-Gault
             equation: Calculated CrCl= ([140-age in years] x [ideal body mass {IBM} in kg])/72 x
             (serum creatinine value in mg/dL), where IBM = IBM (kg) = ([height in cm- 154] × 0.9)
             + (50 if male, 45.5 if female).

          7. Subject must be willing and able to comply with study requirements, remain at the
             clinic, and return to the clinic for the follow-up evaluation, as specified in this
             protocol during the study period.

          8. Able and willing to provide signed informed consent.

        Exclusion Criteria:

        Subjects will not be entered in the study for any of the following reasons:

          1. Prior second-line systemic treatment for GvHD.

          2. Received agents other than steroids for primary treatment of acute GvHD.

          3. Stage 1-2 skin acute GvHD alone (with no other organ involvement).

          4. Acute steroid resistant GvHD beyond 28 days from first-line therapy (primary
             treatment).

          5. Evidence of severe hepatic veno-occlusive disease or sinusoidal obstruction.

          6. Evidence of encephalopathy.

          7. Life expectancy <3 weeks.

          8. Presence of chronic GvHD

          9. Second or subsequent allogeneic transplant.

         10. Previous solid organ transplant (with the exception of a corneal transplant >3 months
             prior to screening).

         11. Relapsed disease after last transplant.

         12. Human immunodeficiency virus positive.

         13. Evidence of lung disease that is likely to require more than 2 liter per minute of O2
             via face mask or an estimated FiO2 of 28% via other delivery methods in order to
             sustain an O2 saturation of 92% within the next 3 days.

         14. Any underlying or current medical or psychiatric condition that, in the opinion of the
             investigator, would interfere with the evaluation of the subject including
             uncontrolled infection, heart failure, pulmonary hypertension. Any other serious
             medical condition, as judged by the investigator, which places the subject at an
             unacceptable risk if he or she were to participate in the study or confounds the
             ability to interpret data from the study.

         15. Administration of any other investigational agents (not approved by the United States
             Food and Drug Agency [FDA] or European Medicines Agency [EMA] for any indication)
             within 30 days of randomization. Participated in any interventional clinical trial for
             an acute GvHD therapeutic agent or for an immunomodulatory drug, within the past 30
             days or within 5 half-lives of the study treatment, whichever is the greater.
             Participated or is currently participating in any bone marrow derived autologous and
             allogeneic stem cell or gene therapy study.

         16. Known hypersensitivity to murine proteins.

         17. Women who are pregnant, breastfeeding or at risk to become pregnant during study
             participation; female subjects of childbearing potential who have not been started on
             an anti-ovulatory regimen prior to initiation of chemo-inductive regimen must test
             negative for pregnancy (serum) at the time of enrollment.

         18. Male and female subjects who do not agree to take adequate measures to avoid pregnancy
             prior to study entry and for the duration of participation in the study (or for at
             least 3 months following the last dose of study drug, whichever is longer) (acceptable
             methods of birth control are described in protocol Section 6.2.1.6).