Thiotepa, Busulfan and Fludarabin for pt With Refractory/Early Relapsed Aggressive B-cell Non Hodgkin Lymphomas (TBF)
Primary Purpose
B-cell Lymphoma Refractory
Status
Unknown status
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Thiotepa
Busulfan
Fludarabin
transplant (HCT)
Cytoreduction
Immunosuppression
Cyclosporine
Methotrexate
ATG
Collection and infusions of Donor PBSC
Sponsored by
About this trial
This is an interventional treatment trial for B-cell Lymphoma Refractory focused on measuring Non Hodgkin lymphomas, Allogeneic Transplantation, Thiotepa, Busulfan, Fludarabin
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.
Sites / Locations
- Città della Salute e della Scienza di TorinoRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
1
Arm 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)
Outcomes
Primary Outcome Measures
Progression free survival
Secondary Outcome Measures
Transplant-related morbidity (TRM) at day +100 and at +365
Overall survival
Incidence of acute and chronic GVHD
Full Information
NCT ID
NCT01786018
First Posted
February 5, 2013
Last Updated
July 7, 2014
Sponsor
Azienda Ospedaliera San Giovanni Battista
1. Study Identification
Unique Protocol Identification Number
NCT01786018
Brief Title
Thiotepa, Busulfan and Fludarabin for pt With Refractory/Early Relapsed Aggressive B-cell Non Hodgkin Lymphomas
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2014
Overall Recruitment Status
Unknown status
Study Start Date
February 2013 (undefined)
Primary Completion Date
February 2015 (Anticipated)
Study Completion Date
February 2015 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Ospedaliera San Giovanni Battista
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Lymphoma Refractory
Keywords
Non Hodgkin lymphomas, Allogeneic Transplantation, Thiotepa, Busulfan, Fludarabin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm 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)
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
TEPADINA®
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
BUSILVEX®
Intervention Type
Drug
Intervention Name(s)
Fludarabin
Other Intervention Name(s)
FLUDARA®
Intervention Type
Procedure
Intervention Name(s)
transplant (HCT)
Intervention Description
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.
Intervention Type
Radiation
Intervention Name(s)
Cytoreduction
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Immunosuppression
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
Day 1 15 mg Days 3, 6, 11 10 mg m2 day IV for GVHD prevention
Intervention Type
Drug
Intervention Name(s)
ATG
Other Intervention Name(s)
Anti-Human Thymocyte Globulin
Intervention Description
(FOR UNRELATED TRANSPLANTS ONLY) Days -3, -2: 2.5 mg /kg/day
Intervention Type
Procedure
Intervention Name(s)
Collection and infusions of Donor PBSC
Intervention Description
Collection and infusions of Donor PBSC
Primary Outcome Measure Information:
Title
Progression free survival
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Transplant-related morbidity (TRM) at day +100 and at +365
Time Frame
1 year
Title
Overall survival
Time Frame
2 years
Title
Incidence of acute and chronic GVHD
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Benedetto Bruno, MD
Phone
+390116336728
Email
benedetto.bruno@unito.it
First Name & Middle Initial & Last Name or Official Title & Degree
Benedetto Bruno, MD
Phone
+390116336728
Email
gismm2001@yahoo.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Benedetto Bruno, MD
Organizational Affiliation
Divisione di Ematologia-Città della Salute e della Scienza di Torino
Official's Role
Principal Investigator
Facility Information:
Facility Name
Città della Salute e della Scienza di Torino
City
Torino
ZIP/Postal Code
10126
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benedetto Bruno, MD
Phone
+390116336728
Email
benedetto.bruno@unito.it
12. IPD Sharing Statement
Learn more about this trial
Thiotepa, Busulfan and Fludarabin for pt With Refractory/Early Relapsed Aggressive B-cell Non Hodgkin Lymphomas
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