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

B-cell Lymphoma Refractory Clinical Trial

— TBF  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01786018
• Other study ID #: TBF2012
• Status: Recruiting
• Phase: Phase 2
• First received: February 5, 2013
• Last updated: July 7, 2014
• Start date: February 2013
• Est. completion date: February 2015

Study information

• Verified date: July 2014
• Source: Azienda Ospedaliera San Giovanni Battista
• Contact: Benedetto Bruno, MD
• Phone: +390116336728
• Email: benedetto.bruno[@]unito.it
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 42
• Est. completion date: February 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• B-cell Lymphoma Refractory
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• Thiotepa

• Busulfan

• Fludarabin

Procedure:
• transplant (HCT)
Transplant will be PBSCs collected as per institutional standard. A portion of the PBSC product will be removed for DLI that is equivalent to 3x10^7 CD3 cells/kg recipient weight and cryopreserved.

Radiation:
• Cytoreduction
Cytoreduction and /or radiation therapy will be given by the referring physician or the attending physician as determined on clinical grounds or to meet eligibility requirements of the protocol for patients with advanced malignancy or to reduce tumor bulk. However, no intensive chemotherapy can be given within three weeks before conditioning.

Drug:
• Immunosuppression
Day -3. Commence cyclosporine at 5.0 mg/kg PO Q12 hours, continue to day +50 and then taper by 5% per week until day +180.
• Cyclosporine
CSP is given based on adjusted body weight, at 5.0 mg/kg PO q12 hours from day -3. If there is nausea and vomiting at anytime during CSP treatment the drug should be given intravenously at the appropriate dose that was used to obtain a therapeutic level. See guidelines for PO to IV conversion below.
• Methotrexate
Day 1 15 mg Days 3, 6, 11 10 mg m2 day IV for GVHD prevention
• ATG
(FOR UNRELATED TRANSPLANTS ONLY) Days -3, -2: 2.5 mg /kg/day

Procedure:
• Collection and infusions of Donor PBSC
Collection and infusions of Donor PBSC

Locations

Country	Name	City	State
Italy	Città della Salute e della Scienza di Torino	Torino

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera San Giovanni Battista

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival		2 years	Yes
Secondary	Transplant-related morbidity (TRM) at day +100 and at +365		1 year	Yes
Secondary	Overall survival		2 years	Yes
Secondary	Incidence of acute and chronic GVHD		2 years	Yes