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

NCT ID: NCT01786018

Last Updated: 2014-07-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-02-28
• Study Completion Date: 2015-02-28

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.

Conditions

B-cell Lymphoma Refractory

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

• 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)

Group Type: EXPERIMENTAL

Thiotepa

Intervention Type: DRUG

Busulfan

Intervention Type: DRUG

Fludarabin

Intervention Type: DRUG

transplant (HCT)

Intervention Type: PROCEDURE

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.

Cytoreduction

Intervention Type: RADIATION

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.

Immunosuppression

Intervention Type: DRUG

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

Intervention Type: DRUG

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

Intervention Type: DRUG

Day 1 15 mg Days 3, 6, 11 10 mg m2 day IV for GVHD prevention

ATG

Intervention Type: DRUG

(FOR UNRELATED TRANSPLANTS ONLY) Days -3, -2: 2.5 mg /kg/day

Collection and infusions of Donor PBSC

Intervention Type: PROCEDURE

Collection and infusions of Donor PBSC

Interventions

Thiotepa

Intervention Type: DRUG

Busulfan

Intervention Type: DRUG

Fludarabin

Intervention Type: DRUG

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.

Intervention Type: PROCEDURE

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.

Intervention Type: RADIATION

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Methotrexate

Day 1 15 mg Days 3, 6, 11 10 mg m2 day IV for GVHD prevention

Intervention Type: DRUG

ATG

(FOR UNRELATED TRANSPLANTS ONLY) Days -3, -2: 2.5 mg /kg/day

Intervention Type: DRUG

Collection and infusions of Donor PBSC

Collection and infusions of Donor PBSC

Intervention Type: PROCEDURE

Other Intervention Names

TEPADINA®; BUSILVEX®; FLUDARA®; Anti-Human Thymocyte Globulin

Eligibility Criteria

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.

• 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).

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.

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Azienda Ospedaliera San Giovanni Battista

OTHER

Sponsor Role: lead

Responsible Party

Benedetto Bruno

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Benedetto Bruno, MD

Role: PRINCIPAL_INVESTIGATOR

Divisione di Ematologia-Città della Salute e della Scienza di Torino

Locations

Città della Salute e della Scienza di Torino

Torino, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Benedetto Bruno, MD

Role: CONTACT

benedetto.bruno@unito.it

+390116336728

Benedetto Bruno, MD

Role: CONTACT

gismm2001@yahoo.com

+390116336728

Facility Contacts

Benedetto Bruno, MD

Role: primary

benedetto.bruno@unito.it

+390116336728

Other Identifiers

TBF2012

Identifier Type: -

Identifier Source: org_study_id