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

NCT02411084 | Terminated Phase 3 Results

• 2 other identifiers: ADN0112015-001360-19
• Study Type: interventional
• Target: 36
• Locations: 7 countries
• Sites: 27

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.

Conditions

Graft vs Host Disease

Keywords

Graft vs Host Disease; Immune System Diseases; Dipeptidyl Peptidase 4; CD4-Positive T-Lymphocytes; Hematopoietic Stem Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• 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

  28 days for OR

Secondary Outcomes (3)

• Number of Participants With Overall Survival (OS) up to 180 Days

  Time frame is up to 180 days

• BEGEDINA Serum Concentrations Pre- and 15 Minutes Post-Infusion

  Time frame is up to Day 28

• Number of Participants With Adverse Events

  The safety parameters were analysed at the end of the study period (Day 180)

Other Outcomes (1)

• Exploratory Objectives

  Time frame is up to 180 days

Study Arms (2)

BEGEDINA® (Begelomab)

EXPERIMENTAL

BEGEDINA® (Begelomab) (murine monoclonal antibody against CD26). Dose is 2.7 mg/m2/day i.v. infusion for 5 consecutive days (Study Days 1, 2, 3, 4, 5) and then single dose on each of Study Days 10, 14, 17, 21, 24 and 28, for a total of 11 doses. BEGEDINA® is supplied as 1 mg/mL concentrate for solution for infusion in vials of 6 mL (5.4 mg of active substance) for reconstitution. The total volume to be administered should be further diluted in 100 mL of 0.9% sodium chloride solution for injection prior to administration. The infusion lasts 60 minutes. Subjects are eligible for a single treatment for flare after study Day 28

Biological: Begelomab

Conventional Second-line Treatment

ACTIVE COMPARATOR

Subjects in the conventional treatment arm will receive a second line treatment, which is to be 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.

Biological: Conventional Second-line Treatment

Interventions

Begelomab BIOLOGICAL

BEGEDINA® (Begelomab) is a murine immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and is produced by biotechnological means.

Also known as: BEGEDINA®

BEGEDINA® (Begelomab)

Conventional Second-line Treatment BIOLOGICAL

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.

Conventional Second-line Treatment

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 and ≤65 years of age.
• Recipient of an allogeneic hematopoietic stem cell transplantation (HSCT). Note: Subjects with GvHD following donor lymphocyte infusion post-HSCT are also eligible
• 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.
• Evidence of previous myeloid engraftment (absolute neutrophil count ≥0.5 x 10\^9/L).
• Karnofsky Performance Status Scale ≥50%.
• 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).
• 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.
• Able and willing to provide signed informed consent.

You may not qualify if:

• Subjects will not be entered in the study for any of the following reasons:
• Prior second-line systemic treatment for GvHD.
• Received agents other than steroids for primary treatment of acute GvHD.
• Stage 1-2 skin acute GvHD alone (with no other organ involvement).
• Acute steroid resistant GvHD beyond 28 days from first-line therapy (primary treatment).
• Evidence of severe hepatic veno-occlusive disease or sinusoidal obstruction.
• Evidence of encephalopathy.
• Life expectancy \<3 weeks.
• Presence of chronic GvHD
• Second or subsequent allogeneic transplant.
• Previous solid organ transplant (with the exception of a corneal transplant \>3 months prior to screening).
• Relapsed disease after last transplant.
• Human immunodeficiency virus positive.
• 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.
• 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.

Sponsors & Collaborators

• Adienne SA: lead
• ADIENNE S.r.l. S.U.: collaborator

Study Sites (27)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

University of Kansas Cancer Center and Medical Pavilion

Westwood, Kansas, 66205, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Hackensack University Medical Center - John Theurer Cancer Center

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke Cancer Center

Durham, North Carolina, 27710, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Huntsman Cancer Center, University of Utah

Salt Lake City, Utah, 84112, United States

Location

Centre Hospitalier Universitaire de Grenoble

La Tronche, 38700, France

Location

Hospital Saint-Louis APHP (Hôpitaux Universitaires Sant-Louis)

Paris, 7545, France

Location

Centre Hospitalier Lyon-Sud

Pierre-Bénite, 69310, France

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Ospedale Casa Sollievo della Sofferenza, IRCCS

San Giovanni Rotondo, Foggia, 71013, Italy

Location

Policlinico S.Orsola Malpighi, AOU di Bologna

Bologna, 40138, Italy

Location

L'IRCCS A.O.U. San Martino - IST

Genova, 16132, Italy

Location

Ospedale San Raffaele

Milan, 20132, Italy

Location

A.O. Universitaria Policlinico Tor Vergata

Roma, 00133, Italy

Location

Policlinico Universitario Agostino Gemelli

Roma, 00168, Italy

Location

Ospedale Molinette

Torino, 10126, Italy

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital Univeristario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitari Politecnic La Fe

Valencia, 46026, Spain

Location

Universitätsspital Basel

Basel, Basel-Stadt (de), 4031, Switzerland

Location

University Hospital Southampton NHS Foundation Trust

Southampton, SO16 6YD, United Kingdom

Location

MeSH Terms

Conditions

Graft vs Host Disease; Immune System Diseases

Limitations and Caveats

This clinical study has prematurely ended, due to the lack of enrollment.

Results Point of Contact

• Title: Renata Palmieri
• Organization: ADIENNE S.A

renata.palmieri@adienne.com

+41.91.210.47.22

Study Officials

• Andrea Bacigalupo, MD

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2015
• First Posted: April 8, 2015
• Study Start: February 1, 2016
• Primary Completion: July 31, 2017
• Study Completion: July 31, 2017
• Last Updated: January 30, 2020
• Results First Posted: January 30, 2020

Record last verified: 2020-01

Locations

FR (3); IT (7); ES (4); DE (1); GB (1); CH (1); US (10)