Graft vs Host Disease
Conditions
Keywords
Graft vs Host Disease, Immune System Diseases, Dipeptidyl Peptidase 4, CD4-Positive T-Lymphocytes, Hematopoietic Stem Cell Transplantation
Brief 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.
Detailed description
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.
Interventions
BIOLOGICALBegelomab
BEGEDINA® (Begelomab) is a murine immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and is produced by biotechnological means.
BIOLOGICALConventional Second-line Treatment
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.
Sponsors
ADIENNE S.r.l. S.U.
Adienne SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response at 28 Days | 28 days for OR | The change in grade from baseline to Study Day 28 (-1/+2 day) was used to determine the response of GvHD to treatment using the following classifications: * Complete response (CR): complete resolution of all signs of GvHD. * Partial response (PR): improvement of 1 overall grade (i.e., change from baseline in IBMTR to a less severe grading). * Stable disease (SD): No change in GvHD grading (i.e., no change from baseline in IBMTR grade). * Disease progression (PD): Deterioration in one overall grade in GvHD (i.e., worsening in IBMTR by at least 1 grade compared to baseline). * Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Survival (OS) up to 180 Days | Time frame is up to 180 days | For this endpoint, no statistical confirmatory test could be performed due to insufficient sample size. |
| BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Time frame is up to Day 28 | The pharmacokinetic (PK) objective for this study was to characterize the serum concentrations of BEGEDINA in subjects with Grades II-IV acute GvHD who have failed to respond to steroid treatment. Data was analyzed before and 15 minutes after infusion. |
| Number of Participants With Adverse Events | The safety parameters were analysed at the end of the study period (Day 180) | The safety parameters were analysed at the end of the study period (Day 180). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Objectives | Time frame is up to 180 days | The exploratory objectives for this study were: * To evaluate the change in quality of life (QoL) from baseline; * To evaluate duration of response; * To evaluate OR by standard-risk and high-risk GvHD at onset |
Countries
France, Germany, Italy, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Out of the 29 sites selected (USA, France, Italy, Spain, Switzerland, UK, Germany) for participation in this study, 22 of them have activated screening and enrolment procedures, and 15 sites have effectively enrolled and randomized participants in the study. The first site approved was in Spain on 07 October 2015.
Pre-assignment details
Out of 184 subjects planned, 37 subjects were screened and 36 subjects were randomized by IVRS in a 1:1 ratio. All subjects signed the informed consent and met all eligibility criteria except one case that had an incomplete screening procedure (some blood tests have not been performed for the screening visit as requested by the protocol).
Participants by arm
| Arm | Count |
|---|---|
| BEGEDINA® (Begelomab) Subjects have received BEGEDINA 2.7 mg/m2/day IV for 5 consecutive days (Study Days 1, 2, 3, 4, 5) and then on Study Days 10, 14, 17, 21, 24 and 28, for a total of 11 doses. A window (+/- 1 day) was permitted for doses from Day 10 to Day 28, however, all efforts have been made to plan these doses with at least 48 hours between doses.
The total volume of BEGEDINA to be administered was diluted in 100 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration. The infusion lasted for 60 minutes.
Begelomab: BEGEDINA® (Begelomab) is a murine immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and is produced by biotechnological means. | 18 |
| Conventional Second-line Treatment Subjects in the conventional treatment arm have received a second line treatment, which were chosen by each center, based on the clinical conditions of the individual subject and according to the standard practice at the study center. Currently no treatments for this life-threatening disease have been approved in either the USA or Europe. The recommendations of the American Society for Blood and Marrow Transplantation (ASBMT) confirm that no treatment for acute steroid-refractory GvHD can be considered gold standard in terms of TRM or survival as results remain unsatisfactory and this approach has been agreed by the FDA and the EMA.
Treatments were 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. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 5 | 4 |
| Overall Study | Lack of Efficacy | 6 | 3 |
| Overall Study | Other reasons | 0 | 5 |
Baseline characteristics
| Characteristic | BEGEDINA® (Begelomab) | Conventional Second-line Treatment | Total |
|---|---|---|---|
| Age, Continuous | 51.4 years STANDARD_DEVIATION 9.06 | 43.5 years STANDARD_DEVIATION 13.74 | 48.3 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 15 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 17 Participants | 34 Participants |
| Region of Enrollment France | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Germany | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Italy | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Spain | 3 participants | 7 participants | 10 participants |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 18 | 8 / 18 |
| other Total, other adverse events | 18 / 18 | 18 / 18 |
| serious Total, serious adverse events | 16 / 18 | 13 / 18 |
Outcome results
Primary
Number of Participants With Overall Response at 28 Days
The change in grade from baseline to Study Day 28 (-1/+2 day) was used to determine the response of GvHD to treatment using the following classifications: * Complete response (CR): complete resolution of all signs of GvHD. * Partial response (PR): improvement of 1 overall grade (i.e., change from baseline in IBMTR to a less severe grading). * Stable disease (SD): No change in GvHD grading (i.e., no change from baseline in IBMTR grade). * Disease progression (PD): Deterioration in one overall grade in GvHD (i.e., worsening in IBMTR by at least 1 grade compared to baseline). * Death
Time frame: 28 days for OR
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BEGEDINA® (Begelomab) | Number of Participants With Overall Response at 28 Days | Complete response | 3 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Overall Response at 28 Days | Stable Disease | 3 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Overall Response at 28 Days | Progressive disease | 1 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Overall Response at 28 Days | Partial Response | 5 Participants |
| Conventional Second-line Treatment | Number of Participants With Overall Response at 28 Days | Progressive disease | 1 Participants |
| Conventional Second-line Treatment | Number of Participants With Overall Response at 28 Days | Complete response | 5 Participants |
| Conventional Second-line Treatment | Number of Participants With Overall Response at 28 Days | Stable Disease | 3 Participants |
| Conventional Second-line Treatment | Number of Participants With Overall Response at 28 Days | Partial Response | 8 Participants |
Secondary
BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion
The pharmacokinetic (PK) objective for this study was to characterize the serum concentrations of BEGEDINA in subjects with Grades II-IV acute GvHD who have failed to respond to steroid treatment. Data was analyzed before and 15 minutes after infusion.
Time frame: Time frame is up to Day 28
Population: The PK report presents the available data for 13 subjects on Begedina arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 21 post-infusion | 271.4 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 1 pre-infusion | 0.0 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 1 post-infusion | 138.6 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 5 pre-infusion | 96.4 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 5 post-infusion | 591.1 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 10 pre-infusion | 6.9 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 10 post-infusion | 289.6 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 14 pre-infusion | 5.3 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 14 post-infusion | 240.7 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 17 pre-infusion | 6.3 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 17 post-infusion | 340.6 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 21 pre-infusion | 0.0 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 24 pre-infusion | 10.9 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 24 post-infusion | 316.0 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 28 pre-infusion | 11.5 ng/ml |
| BEGEDINA® (Begelomab) | BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion | Day 28 post-infusion | 357.0 ng/ml |
Secondary
Number of Participants With Adverse Events
The safety parameters were analysed at the end of the study period (Day 180).
Time frame: The safety parameters were analysed at the end of the study period (Day 180)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BEGEDINA® (Begelomab) | Number of Participants With Adverse Events | Early discontinuation | 16 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Adverse Events | Deaths | 13 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Adverse Events | Non-serious AE | 18 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Adverse Events | SAE | 16 Participants |
| Conventional Second-line Treatment | Number of Participants With Adverse Events | SAE | 13 Participants |
| Conventional Second-line Treatment | Number of Participants With Adverse Events | Early discontinuation | 14 Participants |
| Conventional Second-line Treatment | Number of Participants With Adverse Events | Non-serious AE | 18 Participants |
| Conventional Second-line Treatment | Number of Participants With Adverse Events | Deaths | 8 Participants |
Secondary
Number of Participants With Overall Survival (OS) up to 180 Days
For this endpoint, no statistical confirmatory test could be performed due to insufficient sample size.
Time frame: Time frame is up to 180 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BEGEDINA® (Begelomab) | Number of Participants With Overall Survival (OS) up to 180 Days | Deceased | 13 Participants |
| BEGEDINA® (Begelomab) | Number of Participants With Overall Survival (OS) up to 180 Days | Alive | 5 Participants |
| Conventional Second-line Treatment | Number of Participants With Overall Survival (OS) up to 180 Days | Deceased | 8 Participants |
| Conventional Second-line Treatment | Number of Participants With Overall Survival (OS) up to 180 Days | Alive | 10 Participants |
Other Pre-specified
Exploratory Objectives
The exploratory objectives for this study were: * To evaluate the change in quality of life (QoL) from baseline; * To evaluate duration of response; * To evaluate OR by standard-risk and high-risk GvHD at onset
Time frame: Time frame is up to 180 days
Population: This analysis could not be performed because of the premature discontinuation of the study. No data are available