A Phase I/II, open label, dose escalation study to investigate the pharmacokinetics, pharmacodynamics, safety and clinical activity of begelomab as an initial treatment of acute Graft-versus-Host Disease in combination with standard steroid therapy

Phase 1

Conditions: Acute graft versus host disease after allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion
MedDRA version: 20.1Level: PTClassification code 10066260Term: Acute graft versus host diseaseSystem Organ Class: 10021428 - Immune system disorders
Therapeutic area: Body processes [G] - Immune system processes [G12]

Registration Number: EUCTR2017-002715-34-IT

Lead Sponsor: ADIENNE SA

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 50

Inclusion Criteria

?Age =12 and =70 years old.
?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.
?Subject must be able and willing to provide signed informed consent. For patients aged <18 years, informed consent will be obtained from their parents or legal guardians.
?Patients receiving all types of allogeneic transplantation except patients transplanted with ex vivo T-cell-depleted grafts.
?Patients with acute GvHD Grade II, III and IV diagnosed after allogeneic hematopoietic transplant using either bone marrow (BM), peripheral blood stem cells (PBSC) or cord blood (CB), or after donor lymphocyte infusion (DLI).
A confirmatory biopsy is required, if clinically feasible, to confirm diagnosis of skin and gastrointestinal GvHD, and is recommended when feasible in case of isolated liver involvement. Reasons for any omission of biopsy will be documented in the CRF.
?De novo acute GvHD requiring systemic therapy. GvHD is defined as the presence of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting in a context in which acute GvHD is likely to occur and where other aetiologies such as drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled out.
A confirmatory biopsy is required, if clinically feasible, to confirm diagnosis of skin and gastrointestinal GvHD, and is recommended when feasible in case of isolated liver involvement. Reasons for any omission of biopsy will be documented in the CRF.
?The patient must have had no previous systemic immune suppressive therapy for treatment of acute GvHD except for a maximum 24 hours of prior corticosteroid therapy at =2.0 mg/kg methylprednisolone or equivalent after the onset of acute GvHD.
?Evidence of myeloid engraftment (absolute neutrophil count (ANC) = 500/µL).
?The disease for which the patient underwent to HSCT must be in remission.
?Patients with adequate renal reserve as defined by serum creatinine = 3× upper limit of normal (ULN) or calculated creatinine clearance (CLcr) =30 mL/min using the Cockroft-Gault equation (1976).
?Respiratory function: forced vital capacity (FVC) or forced expiratory volume in one second (FEV1) = 50% of predicted.
?Cardiac ejection fraction > 40%.
?Lansky performance score = 70% for patients aged <16 years or Karnofsky performance score =50% for patients aged = 16 years).
?Life expectancy of greater than 1 month.
?Women of child-bearing potential and men must agree to take adequate contraceptive measures in order to avoid any pregnancies of their sexual partners during the course of the study (or for at least 3 months following the last dose of study drug, whichever is longer). Acceptable methods of birth control include oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device IUD) or intrauterine system (IUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/ cream/suppository. Abstinence is only considered an acceptable form of contraception when it is the usual life style of an individual.
?Women must have a negative pregnancy test at Screening and at Baseline and must not be breastfeeding.

Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects

Exclusion Criteria

?Patients transplanted with ex vivo T-cell-depleted grafts.
?Patients with signs of steroid-resistance.
?Participants with manifestations of chronic GvHD.
?Participants with acute/chronic GvHD overlap syndrome.
?Patient with evidence of relapsed/persistent malignancy.
?Patients with adequate renal reserve as defined by serum creatinine = 3× ULN or calculated creatinine clearance (CLcr) = 30 mL/min using the Cockroft-Gault equation.
?Lansky performance score =70 for patients aged <16 years or Karnofsky performance score =50% for patients aged = 16 years).
?Severe organ dysfunction unrelated to underlying GVHD, including:
-Cholestatic disorders or unresolved veno-occlusive disease (VOD) of the liver.
-Clinically significant or uncontrolled cardiac disease.
-Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.
?Patients with severe hepatic veno-occlusive disease or sinusoidal obstruction syndrome who in the judgement of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment
?Any underlying or current medical or psychiatric condition that, in the opinion of the investigator, would interfere with the evaluation of the subject including, but not limited to symptomatic congestive heart failure (New York Heart Association [NYHA] Class III to IV), unstable angina pectoris or cardiac arrhythmia. 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.
?Patients with known central nervous system (CNS) involvement.
?Pleural effusion or ascites > 1 liter
?Patients with uncontrolled bacterial, viral or fungal infections
?Uncontrolled diabetes at the time of cytoreduction.
?Evidence of HIV seropositivity and/or positive PCR assay, HTLV1 / HTLV2 seropositivity.
?Evidence of seropositivity for hepatitis B virus surface antigen (HBsAg) and/or anti-hepatitis C virus (anti-HCV) antibodies.
Serologic positivity in the absence of detectable HBV or HCV DNA/RNA will not be exclusion criteria.
?Evidence of a clinically relevant CMV-viremia.
Clinically relevant CMV-viremia is defined as detection of viral load =5000 copies/mL in whole blood, as measured by quantitative PCR.
?A history of prolonged QTc syndrome.
?Administration of any other investigational agents (not approved by the United States Food and Drug Administration Agency [FDA] or European Medicines Agency [EMA] for any indication) within 4 weeks prior to enrolment. Participation in any clinical trial for prevention of acute GvHD or within 5 half-lives of the study treatment (whichever is longer) within 4 weeks of the screening visit.
?Known hypersensitivity to murine proteins.
?Women who are pregnant, breastfeeding or at risk to become pregnant during study participation; female patients 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 Baseline Visit.
?Unwillingness to use effective contraceptive measures up to 3 months after the end of study drug administration (females and males). Acceptable methods of birth control include oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device IUD) or intrauterine system (IUS), barrier methods of contracept