T&B Depletion Non Malignant

Franco Locatelli

Status and phase: Unknown; Phase 2

Conditions: Graft Versus Host Disease

Treatments: Drug: Thiotepa; Drug: Cyclosporine A; Biological: polyclonal antibody; Drug: Methotrexate; Drug: Rituximab; Drug: Treosulfan; Drug: Fludarabine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01810926

OPBG_361.11

2011-004730-34 (EudraCT Number)

Details and patient eligibility

About

• The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Both safety and efficacy of the treatment will be assessed, in particular in respect to the clinical status of the patient, i.e. prevention of graft failure and chronic GvHD and of Ebstein Barr virus (EBV) viremia for MUD patients.

The conditioning proposed combines myeloablative drugs with a favorable safety profile such as treosulfan, thiotepa (Tepadina®) and fludarabine with the intent to reduce the traditional immediate and late toxicity of busulfan and cyclophosphamide.

Full description

For patients transplanted from a MRD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

• primary and secondary graft failure,
• aGVHD II-IV,
• cGVHD,
• death, whichever occurs first.

For patients transplanted from a MUD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

• aGVHD II-IV,
• EBV viremia, whichever occurs first.

Enrollment: 130 estimated patients

Sex: All

Ages: 28 days to 64 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• non malignant haematological and inherited metabolic disorders benefiting from an allogeneic HSCT conditioned with a myeloablative regimen
• Availability of a matched related donor (MRD) or Matched Unrelated Donor (MUD)
• Lansky or Karnofsky Index ≥ 60
• Inherited metabolic disorders: DQ ≥ 70 (+ MRI Loes score ≤ 9 for adrenoleukodystrophy)
• Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
• Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
• Heart shortening fraction (left-ventricle) > 28 % or LVEF > 55%
• Serum bilirubin ≤ 1.5 × ULN (except for Wolman disease),
• AST and ALT ≤ 2.5 × ULN (except for thalassemic syndromes and Wolman disease)
• Pulmonary function: if cooperative: FEV1 and FVC on pulmonary function testing > 60 %; if non cooperative: pulse oximetry > 95 % in room air
• Availability of autologous back up marrow (> 2 x 108 TNC+ cells/kg or > 2 x 106 CD34+ cells/kg) for MUD
• Adequate contraception in female patients of child-bearing potential
• Signed informed consent

Exclusion criteria

• Any malignancy
• Liver cirrhosis evidenced on liver histology (performed in suspicious cases or in case of Wolman disease)
• HIV- positivity
• Clinically significant pleural effusion or ascites
• Pregnancy or lactation
• Known hypersensitivity to trial drugs
• Participation in another experimental drug trial in the 2 months preceding enrollment
• Non-cooperative behaviour or non-compliance
• Previous HSCT

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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130 participants in 4 patient groups

MRD-Regimen&Polyclonal antibody

Experimental group

Description:

Patients MRD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 \& ATG-Fresenius S® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2

Treatment:

Drug: Methotrexate

Drug: Fludarabine

Drug: Treosulfan

Drug: Methotrexate

Biological: polyclonal antibody

Drug: Cyclosporine A

Drug: Thiotepa

MRD-Regimen

Sham Comparator group

Description:

Patients receiving stem cell transplantation from a matched related donors (MRD) will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²) + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 (total dose of 150 mg/m²) after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals (total dose of 8 mg/kg)+ Cyclosporine A iv at a starting dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL (In the absence of GvHD CSA will be tapered after day + 180 and stopped at 9-12 months) + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6

Treatment:

Drug: Methotrexate

Drug: Fludarabine

Drug: Treosulfan

Drug: Methotrexate

Drug: Cyclosporine A

Drug: Thiotepa

MUD-Regimen & Rituximab

Experimental group

Description:

Patients MUD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 \& Rituximab in a single infusion of 200 mg/m2 on day -1

Treatment:

Drug: Methotrexate

Drug: Fludarabine

Drug: Treosulfan

Drug: Rituximab

Drug: Methotrexate

Biological: polyclonal antibody

Drug: Cyclosporine A

Drug: Thiotepa

MUD-Regimen

Sham Comparator group

Description:

Patients MUD will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2

Treatment:

Drug: Methotrexate

Drug: Fludarabine

Drug: Treosulfan

Drug: Methotrexate

Biological: polyclonal antibody

Drug: Cyclosporine A

Drug: Thiotepa