Clinical trial NCT01786018: Thiotepa, Busulfan and Fludarabin for pt With Refractory/Early Relapsed Aggressive B-cell Non Hodgkin Lymphomas
Official title: Allogeneic Transplantation After a Conditioning With Thiotepa, Busulfan and Fludarabin for the Treatment of Refractory/Early Relapsed Aggressive B-cell Non Hodgkin Lymphomas: a Phase II Multi-Center Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: B-cell Lymphoma Refractory
Keywords: Non Hodgkin lymphomas
Allogeneic Transplantation
Thiotepa
Busulfan
Fludarabin
Lead sponsor: Azienda Ospedaliera San Giovanni Battista
Sponsor class: OTHER
First posted: 2013-02-07
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Progression free survival
timeFrame: 2 years
Secondary outcomes:
measure: Transplant-related morbidity (TRM) at day +100 and at +365
timeFrame: 1 year
measure: Overall survival
timeFrame: 2 years
measure: Incidence of acute and chronic GVHD
timeFrame: 2 years
Other outcomes:
Locations:
city: Torino
country: Italy
facility: Città della Salute e della Scienza di Torino
Study officials:
affiliation: Divisione di Ematologia-Città della Salute e della Scienza di Torino
name: Benedetto Bruno, MD
role: PRINCIPAL_INVESTIGATOR
References: