Safety and feasibility of ATIR201, a T-lymphocyte enriched leukocyte preparation depleted of host alloreactive T-cells, in patients with beta-thalassemia major who received a hematopoietic stem cell transplantation from a haploidentical donor

Phase 1

• Conditions: Patients with beta-thalassemia major who are eligible for a haploidentical HSCT; MedDRA version: 19.0 Level: LLT Classification code 10054661 Term: Thalassemia major System Organ Class: 100000004850; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2016-002959-17-GB
• Lead Sponsor: Kiadis Pharma Netherlands B.V.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-09-07
• Last Update Posted: 10 December 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 10

Inclusion Criteria

Patient Inclusion Criteria:
• Confirmed diagnosis of beta-thalassemia major:
- Hypertransfusion program with eight or more red blood cell (RBC) transfusions a year and a confirmed annual transfusion of = 100 ml/kg/year.
- Genotype consistent with clinical diagnosis of beta-thalassemia major (including hemoglobin E-beta-thalassemia genotype)
- Iron chelation therapy initiated, or not yet initiated but at risk of transfusional iron overload
• Lansky / Karnofsky performance score > 70%
• Eligible for haploidentical stem cell transplantation according to the investigator taking into account the feasibility of transplanting patients with pre-existing antibodies (e.g. anti-A, anti-B, and/or other anti-donor red cell antibodies or known presence of HLA antibodies against the non-shared donor haplotype)
• Male or female, age = 2 years and = 25 years

Donor Inclusion Criteria:

• Haploidentical family donor with at least 4 out of 8 or 5 out of 10 matches at the HLA- A, -B , -C, -DR, and/or DQ loci as determined by high resolution typing
• Male or female, age = 16 and = 75 years (If applicable, local legal requirements for
donors under the age of 18 will be followed)
• Eligible for donations of human blood and blood components according to local requirements and regulations
• Fit to receive granulocyte colony-stimulating factor (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within standards)
• Eligible for donation according to the transplantation center
Are the trial subjects under 18? yes
Number of subjects for this age range: 7
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 3
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

Exclusion Criteria Patient:

• Availability of a fully matched related or unrelated donor following a donor search, which might have been initiated before screening.
• Patient assigned to Pesaro risk class 3
• Symptomatic cardiac failure: left ventricular ejection fraction at rest < 50% and no improvement with exercise, or shortening fraction < 26% (evaluated by echocardiogram or MUGA)
• Hepatic failure: > 5 times the upper limit of normal range (ULN) for age of AST or > 2.5 times the ULN for age of total serum bilirubin
• Renal function (creatinine clearance or GFR) < 50% of the lower limit of normal (LLN) for age
• Symptomatic pulmonary failure: DLCO, FEV1, or FEC (diffusion capacity) < 50% of predicted (corrected for hemoglobin); if unable to perform a pulmonary function test, oxygen saturation < 85% on room air
• Positive pregnancy test (females of childbearing age only)
• Positive test for HIV-1 or HIV-2
• Active viral, bacterial, fungal, or parasitic infection, including hepatitis B, hepatitis C
• Prior HSCT for beta-thalassemia major
• Known allergy to any of the components of ATIR201 (e.g., dimethyl sulfoxide)
• Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study

Donor Exclusion Criteria:

• Positive pregnancy test or nursing (females of childbearing age only)
• Positive viral test for HIV-1, HIV-2, HBV, HCV, or Treponema pallidum
• Hemoglobin S = 50%, or presence of beta-thalassemia intermedia
• History of congestive heart failure, unstable angina, or history of stroke

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<br> Main Objective: The objective of the study is to evaluate the safety and feasibility of ATIR201 in patients with beta-thalassemia major who received a T-cell depleted haploidentical hematopoietic stem cell transplantation (HSCT).<br> Safety and tolerability will be primarily evaluated by the occurrence of acute graft-versus- host disease (GVHD) grade III/IV within 180 days post HSCT.<br> Efficacy will be primarily evaluated by transfusion-free survival (TFS), occurrence of severe infections, and time to T-cell reconstitution, taking into account hematologic and sustained engraftment.<br> ;Secondary Objective: Not applicable;Primary end point(s): Incidence of acute graft versus host disease (GvHD) grade III/IV within 180 days post HSCT.;Timepoint(s) of evaluation of this end point: 180 days post HSCT

Secondary Outcome Measures

Name	Time	Method
<br> Secondary end point(s): Secondary safety endpoints:<br> • Occurrence of acute and chronic GVHD (all grades/severities)<br> • Occurrence of graft rejection<br> • Occurrence of prolonged donor red cell aplasia<br> • Donor chimerism<br><br> Secondary efficacy endpoints:<br> • Transfusion-free survival (TFS)<br> • Occurrence of severe (NCI grade 3-5) infections<br> • Time to T-cell reconstitution, defined as the time to CD3+ > 0.2×10E9/l in peripheral blood (at two consecutive measurements; time to first measurement)<br> • Overall survival (OS), defined as the time from HSCT until death from any cause<br> • Transplant-related mortality (TRM), defined as death due to causes other than disease recurrence<br> ;Timepoint(s) of evaluation of this end point: Up to 12 months post HSCT