Study of BEGEDINA® vs "Conventional Treatment" for Treating Steroid-Resistant Acute GvHD

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.

This is a prospective, phase II/III, randomized clinical study to compare the efficacy and safety of BEGEDINA® (Begelomab) versus "conventional treatment" for treating steroid-resistant acute graft versus host disease (GvHD). Despite prophylactic treatment, GvHD still develops in up to 30% of allogeneic hemopoietic stem cell transplant (HSCT) recipients. GvHD is a life-threatening and complex immunological disease that may be acute or chronic. Acute GvHD affects mainly the skin, liver and gastrointestinal (GI) tissues with long-term survival directly related to the severity of skin, liver and gut involvement. First line treatment for patients with acute GvHD (Grade II or higher) is the immunosuppressive corticosteroid methylprednisolone. Although effective in over 50% of patients, durable responses are observed in only a third of patients and it also confers a risk of severe infection. Steroid-resistant acute GvHD is associated with a high rate of morbidity and mortality, primarily from infections and/or multi-organ failure. Despite this, there are no authorized treatments for non-responders and GvHD remains largely an untreatable disease with limited survival and thus a great unmet therapeutic need. BEGEDINA® (Begelomab) is a murine immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and is produced by biotechnological means and is a new potential therapeutic approach. BEGEDINA® has been shown to bind to CD26 which is present on a subset of CD4+ T helper lymphocytes leading to down-regulation of CD26 signaling and inhibition of immune response and thus therapeutic improvements. BEGEDINA has been investigated in two completed clinical studies: a pilot study and a dose-finding study and so far showing promising efficacy, safety and tolerability.

The primary objective for this study is therefore to determine the efficacy of BEGEDINA® versus conventional therapy in steroid-resistant acute GvHD. To satisfy this objective, two co primary hypothesis will be tested. The first is that the overall response rate consisting of the Complete Responders and the Partial Responders (CR+PR) at Study Day 28 will be higher in the BEGEDINA® treated subjects. The second is that the incidence of transplant-related mortality (TRM) at 6 months will be reduced in those subjects treated with BEGEDINA® versus those treated with conventional therapy. Additional secondary efficacy endpoints will also be assessed as a measure of effectiveness. In addition, some pharmacokinetics assessments will be performed. Adverse events (AEs) will be coded using MedDRA and the frequency, causality and intensity of AEs will be compared to conventional therapies. Further safety analysis will also include laboratory findings, vital signs, immunogenicity and other assessments. Finally, some exploratory analysis will also be performed.

This will be a prospective, multicenter, randomized, open-label, phase II/III clinical study in which subjects will be randomly assigned in a 1:1 ratio to receive BEGEDINA® treatment or the best conventional treatment available in their territory as no second line therapy is currently approved. It is planned to enroll 184 male or female adult subjects with an upper age limit of 65 years with steroid-resistant acute GvHD. BEGEDINA® will be administered at a dose of 2.7 mg/m2/day for 5 consecutive days from Study Day 1 through to Study Day 5, and on Study Days 10, 14, 17, 21, 24, and 28. Thus, the expected duration for each subject will be approximately 12 months. The final statistical analysis plan (SAP) will be finalized prior to database lock. Baseline characteristics of the subject sample will be described using summary statistics. All statistical tests will be conducted at a 2-sided significance level of 5% unless specifically specified. Multiple Imputation methods will be used as the primary method for accounting for missing data.

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).