Thiotepa, Busulfan and Fludarabin for pt With Refractory/Early Relapsed Aggressive B-cell Non Hodgkin Lymphomas (TBF)

Azienda Ospedaliera San Giovanni Battista

Status and phase

Unknown

Phase 2

Conditions

B-cell Lymphoma Refractory

Treatments

Drug: Immunosuppression

Drug: Thiotepa

Drug: Methotrexate

Drug: Cyclosporine

Procedure: transplant (HCT)

Procedure: Collection and infusions of Donor PBSC

Drug: ATG

Drug: Busulfan

Drug: Fludarabin

Radiation: Cytoreduction

Study type

Interventional

Funder types

Other

Identifiers

NCT01786018

TBF2012

Details and patient eligibility

About

The purpose of this study is to evaluate progression free survival, transplant-related morbidity (TRM) at day +100 and at +365, overall survival and incidence of acute and chronic GVHD in refractory/early relapsed aggressive B-cell non Hodgkin lymphomas patients treated with allogeneic Transplantation after a conditioning with Thiotepa, Busulfan and fludarabin.

Full description

In the present study, it is hypothesised that patients with aggressive B cell lymphomas refractory to or relapsed early (within 12 months) after the completion of standard first-line immunoProtocol TBF2012 Version 1, 20 Nov 2012 9 chemotherapy can benefit from de-bulking salvage therapy (i.e. R-DHAP + bortezomib) followed by an allograft to improve progression-free survival.

Patient inclusion criteria

Patients with refractory/relapsed aggressive B-cell non Hodgkin lymphomas after frontline therapy.
Patients with stable disease or partial or complete remission (PET-negative) after salvage therapy
Patients younger than 65 years old
A fully HLA-identical sibling or matched unrelated donor is available. Patients with one antigen mismatched donors can be considered
Patient must be competent to give consent

Patient exclusion criteria

Patients treated with an autologous transplant as salvage therapy
Patients with progressive lymphomas despite conventional therapies
Patients with progressive lymphomas despite conventional therapies
Uncontrolled CNS involvement with disease
Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
Females who are pregnant or breastfeeding
Organ dysfunction defined as follows:
- Cardiac function: ejection fraction <30% or uncontrolled cardiac failure
- Pulmonary: DLCO <40% predicted
- Liver function abnormalities: elevation of bilirubin to > 3 mg/dl and/or transaminases >4 the upper limit of normal
- Renal: creatinine clearance <50 cc/min (24 hour urine Protocol TBF2012 Version 1, 20 Nov 2012 6 collection)
Karnofsky performance score < 60%
Patients with poorly controlled hypertension despite multiple antihypertensives
Documented fungal disease that is progressive despite treatment
Viral infections: HIV positive patients.
Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBV DNA test will be performed and if positive the subject will be excluded.
Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result
Psychiatric disorders or psychosocial problems which in the opinion of the primary physician or Principal Investigator would place the patient at unacceptable risk from this regimen.
Patients with active non-hematologic malignancies (except nonmelanoma skin cancers).
Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a >20% risk of disease recurrence. Donor inclusion criteria:
Related or unrelated HLA identical donors who are in good health and have no contra-indication to donation. One antigen HLAmismatched (9/10 match) donors will also be considered.
No contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by G-CSF at a dose of 10-12 μg/kg of body weight.
Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). Donor exclusion criteria:
Age < 18 years.
Identical twin.
Pregnancy.
Infection with HIV.
Inability to achieve adequate venous access.
Known allergy to filgrastin (G-CSF).
Current serious systemic illness.

Donor inclusion criteria:

Related or unrelated HLA identical donors who are in good health and have no contra-indication to donation. One antigen HLAmismatched (9/10 match) donors will also be considered.
No contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by G-CSF at a dose of 10-12 μg/kg of body weight.
Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). Donor exclusion criteria:
Age < 18 years.
Identical twin.
Pregnancy.
Infection with HIV.
Inability to achieve adequate venous access.
Known allergy to filgrastin (G-CSF).
Current serious systemic illness.

Donor inclusion criteria:

Related or unrelated HLA identical donors who are in good health and have no contra-indication to donation. One antigen HLAmismatched (9/10 match) donors will also be considered.
No contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by G-CSF at a dose of 10-12 μg/kg of body weight.
Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). Donor exclusion criteria:
Age < 18 years.
Identical twin.
Pregnancy.
Infection with HIV.
Inability to achieve adequate venous access.
Known allergy to filgrastin (G-CSF).
Current serious systemic illness.

Enrollment

42 estimated patients

Sex

All

Ages

18 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Patient inclusion criteria:

Patients with refractory/relapsed aggressive B-cell non Hodgkin lymphomas after frontline therapy.
Patients with stable disease or partial or complete remission (PET-negative) after salvage therapy
Patients younger than 65 years old
A fully HLA-identical sibling or matched unrelated donor is available. Patients with one antigen mismatched donors can be considered
Patient must be competent to give consent.

Patient exclusion criteria:

Patients treated with an autologous transplant as salvage therapy
Patients with progressive lymphomas despite conventional therapies
Patients with progressive lymphomas despite conventional therapies
Uncontrolled CNS involvement with disease
Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
Females who are pregnant or breastfeeding
Organ dysfunction defined as follows:
- Cardiac function: ejection fraction <30% or uncontrolled cardiac failure
- Pulmonary: DLCO <40% predicted
- Liver function abnormalities: elevation of bilirubin to > 3 mg/dl and/or transaminases >4x the upper limit of normal
- Renal: creatinine clearance <50 cc/min (24 hour urine collection)
Karnofsky performance score < 60%
Patients with poorly controlled hypertension despite multiple antihypertensives
Documented fungal disease that is progressive despite treatment
Viral infections: HIV positive patients.
Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBV DNA test will be performed and if positive the subject will be excluded.
Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result
Psychiatric disorders or psychosocial problems which in the opinion of the primary physician or Principal Investigator would place the patient at unacceptable risk from this regimen.
Patients with active non-hematologic malignancies (except non-melanoma skin cancers).
Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a >20% risk of disease recurrence.

Donor inclusion criteria:

Related or unrelated HLA identical donors who are in good health and have no contra-indication to donation. One antigen HLA-mismatched (9/10 match) donors will also be considered.
No contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by G-CSF at a dose of 10-12 mg/kg of body weight.
Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian).

Donor exclusion criteria:

Age < 18 years.
Identical twin.
Pregnancy.
Infection with HIV.
Inability to achieve adequate venous access.
Known allergy to filgrastin (G-CSF).
Current serious systemic illness.

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

42 participants in 1 patient group

Experimental group

Description:

* Thiotepa 5 mg/kg/day on days -7, -6 (Total Dose 10 mg/kg) * Busulfan (i.v.) 3.2 mg/kg on days -5,-4,-3 (Total Dose 9.6 mg/kg) * Fludarabin: 50 mg/m2/day on days -5,-4,-3 (Total Dose 150 mg/m2)

Treatment:

Drug: Fludarabin

Drug: ATG

Drug: Busulfan

Radiation: Cytoreduction

Drug: Immunosuppression

Drug: Methotrexate

Procedure: Collection and infusions of Donor PBSC

Procedure: transplant (HCT)

Drug: Cyclosporine

Drug: Thiotepa