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Reduced Intensity Conditioning (RIC) Regimen and Post-transplant Cyclophosphamide in Haploidentical Bone Marrow Transplantation in in Patients With Poor Prognosis Lymphomas

Primary Purpose

Lymphoma

Status
Unknown status
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Thiotepa
Fludarabine
Cyclophosphamide
Sponsored by
Istituto Clinico Humanitas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring lymphoma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • Signed and dated IEC-approved informed consent
  • Age ≥ 18-70 years old.
  • Performance Status Karnofsky ≥ 80% (see appendix B)
  • HLA typing will be performed at high resolution (allele level) for the HLA-A, HLA -B, HLA Cw, HLA-DRB1, and HLA-DQB1 loci. A minimum match of 5/10 is required. An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant.
  • The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.

  • Patients with lymphoma (any histology) relapsed after high dose chemotherapy and in partial remission, complete remission or stable disease after the last CT line.

    1. Hodgkin's lymphoma: Patients refractory to at least 2 CT lines, and included in tandem auto-allo program
    2. Diffuse large B cell lymphoma: Refractory to second line salvage chemotherapy (patients in partial remission, stable disease or progressive). These patients have to be in partial remission, complete remission or stable disease after one o more further CT line.
    3. Peripheral T cell lymphoma: Patients failing to achieve a complete remission after first line CT.
    4. Low grade lymphomas (follicular and non follicular: Patients refractory to rituximab containing regimens. Patients relapsing after at least 2 lines CT. The duration of remission should be < 1 year.
    5. Chronic lymphatic leukemia: Patients with refractory or relapsing (response duration < 1 year) disease after R-Fludarabine CT
    6. Mantle cell lymphoma: Patients relapsing or refractory after first line conventional CT.
  • Absence of HLA identical sibling and 10/10 unrelated donor
  • Patients with adequate physical function as measured by:

Cardiac: Left ventricular ejection fraction at rest must be ≥ 40% Hepatic: Bilirubin ≤ 2.5 mg/dL; and ALT, AST, and Alkaline Phosphatase ≤ 5 x ULN.

Renal: Creatinine clearance or GFR ≥ 50 mL/min/1.73 m2. Pulmonary: FEV1, FVC, DLCO ≥ 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation ≥ 92% on room air.

Exclusion Criteria:

  • Presence of HLA-matched, related donor (HLA-A, -B, -DRB1)
  • Presence of matched unrelated donor (10/10), available on time.
  • Pregnancy or breast-feeding.
  • Evidence of HIV infection or known HIV positive serology.
  • Current uncontrolled bacterial, viral or fungal infection
  • Evidence of progression of clinical symptoms or radiologic findings.
  • Prior allogeneic hematopoietic stem cell transplant.
  • Central Nervous System (CNS) lymphoma localization

Sites / Locations

  • Istituto Clinico HumanitasRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

RIC regimen

Arm Description

Thiotepa, Fludarabine, Cyclophosphamide pre- and post- transplantation.

Outcomes

Primary Outcome Measures

Procedure activity
1-year Progression Free Survival (PFS) to evaluate the activity of the procedure (taking into account an excess of toxicity). It is assumed that at 1-year a proportion of patients progression free of 20% or lower will be considered to be clinically unworthy, whereas a proportion of 40% or higher will be assumed to be of potential interest.

Secondary Outcome Measures

Neutrophils recovery
Neutrophils will be measured at different time points of increasing lenght up to 1 year after transplant and then if clinically indicated
Platelets recovery
Platelets will be measured at different time points of increasing lenght up to 1 year after transplant and then if clinically indicated
Incidence of graft failure
Cumulative incidence of acute and chronic GVHD
Incidence of infections
Possible infections will be monitored for a time period of 1 year post-transplantation and then if clinically required
Cumulative incidence of relapse/progression
Treatment related mortality (TRM)
Immunological reconstitution
T, B and NK subsets will be analysed in deep using cytofluorimetry and functional tests.

Full Information

First Posted
January 28, 2014
Last Updated
January 29, 2014
Sponsor
Istituto Clinico Humanitas
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1. Study Identification

Unique Protocol Identification Number
NCT02049580
Brief Title
Reduced Intensity Conditioning (RIC) Regimen and Post-transplant Cyclophosphamide in Haploidentical Bone Marrow Transplantation in in Patients With Poor Prognosis Lymphomas
Official Title
Multi-center, Phase II Study to Assess the Safety and Efficacy of Haploidentical Bone Marrow Transplantation Using Reduced Intensity Conditioning(RIC)Regimen and Post-transplant Cyclophosphamide,in Patients With Poor Prognosis Lymphomas
Study Type
Interventional

2. Study Status

Record Verification Date
January 2014
Overall Recruitment Status
Unknown status
Study Start Date
July 2013 (undefined)
Primary Completion Date
August 2016 (Anticipated)
Study Completion Date
November 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Istituto Clinico Humanitas

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Study to test feasibility and efficacy of T-replete Bone Marrow (BM), infused after a RIC regimen and post-transplantation Cyclophosphamide (Cy), in patients with poor prognosis lymphomas.
Detailed Description
Allogeneic stem cell transplantation (ALLO) is the treatment of choice for many hematological diseases. However, HLA identical donor (sibling or unrelated) is available for 50-60% of patients and alternative donors are needed. Haploidentical donors have been used for many years, mostly after extensive T-cell depletion of peripheral stem cell, to avoid Graft Versus Host Disease (GVHD). Recently, promising data have been reported with haploidentical transplantation using T-replete bone marrow (BM) and high-dose cyclophosphamide (Cy) post-transplantation. However, the conditioning regimen did not contain drugs active against hemopathies, enhancing the relapse risk. In this study, the investigators want to test the feasibility and efficacy of T-replete BM, infused after a RIC regimen and post-transplantation Cy, in patients with poor prognosis lymphoproliferative diseases. The RIC regimen consisted of modified regimen used in different studies conducted in Italy on behalf GITMO.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma
Keywords
lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
RIC regimen
Arm Type
Experimental
Arm Description
Thiotepa, Fludarabine, Cyclophosphamide pre- and post- transplantation.
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
Tepadina
Intervention Description
Thiotepa (10 mg/kg /day) will be administered every 12 h, at day -6
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine (30mg/m2/day x 4 days) will be dosed according to renal function. For decreased creatinine clearance (CCr) (≤ 61 mL/min) Fludarabine dosage should be reduced as follows: CCr 46-60 mL/min, fludarabine = 24 mg/ m2/day
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Endoxan
Intervention Description
Pre-transplantation Cyclophosphamide(Cy) 30 mg/kg/day will be administered as a 1-2 hour intravenous infusion with a high volume fluid flush on Days -5. Cy will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125% of IBW, in which case the drug will be dosed according to the Adjusted IBW (AIBW) Cyclophosphamide [50 mg/kg/day IBW] will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).
Primary Outcome Measure Information:
Title
Procedure activity
Description
1-year Progression Free Survival (PFS) to evaluate the activity of the procedure (taking into account an excess of toxicity). It is assumed that at 1-year a proportion of patients progression free of 20% or lower will be considered to be clinically unworthy, whereas a proportion of 40% or higher will be assumed to be of potential interest.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Neutrophils recovery
Description
Neutrophils will be measured at different time points of increasing lenght up to 1 year after transplant and then if clinically indicated
Time Frame
1 year
Title
Platelets recovery
Description
Platelets will be measured at different time points of increasing lenght up to 1 year after transplant and then if clinically indicated
Time Frame
1 year
Title
Incidence of graft failure
Time Frame
1 year
Title
Cumulative incidence of acute and chronic GVHD
Time Frame
1 year
Title
Incidence of infections
Description
Possible infections will be monitored for a time period of 1 year post-transplantation and then if clinically required
Time Frame
1 year
Title
Cumulative incidence of relapse/progression
Time Frame
1 year
Title
Treatment related mortality (TRM)
Time Frame
1 year
Title
Immunological reconstitution
Description
T, B and NK subsets will be analysed in deep using cytofluorimetry and functional tests.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Signed and dated IEC-approved informed consent Age ≥ 18-70 years old. Performance Status Karnofsky ≥ 80% (see appendix B) HLA typing will be performed at high resolution (allele level) for the HLA-A, HLA -B, HLA Cw, HLA-DRB1, and HLA-DQB1 loci. A minimum match of 5/10 is required. An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Patients with lymphoma (any histology) relapsed after high dose chemotherapy and in partial remission, complete remission or stable disease after the last CT line. Hodgkin's lymphoma: Patients refractory to at least 2 CT lines, and included in tandem auto-allo program Diffuse large B cell lymphoma: Refractory to second line salvage chemotherapy (patients in partial remission, stable disease or progressive). These patients have to be in partial remission, complete remission or stable disease after one o more further CT line. Peripheral T cell lymphoma: Patients failing to achieve a complete remission after first line CT. Low grade lymphomas (follicular and non follicular: Patients refractory to rituximab containing regimens. Patients relapsing after at least 2 lines CT. The duration of remission should be < 1 year. Chronic lymphatic leukemia: Patients with refractory or relapsing (response duration < 1 year) disease after R-Fludarabine CT Mantle cell lymphoma: Patients relapsing or refractory after first line conventional CT. Absence of HLA identical sibling and 10/10 unrelated donor Patients with adequate physical function as measured by: Cardiac: Left ventricular ejection fraction at rest must be ≥ 40% Hepatic: Bilirubin ≤ 2.5 mg/dL; and ALT, AST, and Alkaline Phosphatase ≤ 5 x ULN. Renal: Creatinine clearance or GFR ≥ 50 mL/min/1.73 m2. Pulmonary: FEV1, FVC, DLCO ≥ 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation ≥ 92% on room air. Exclusion Criteria: Presence of HLA-matched, related donor (HLA-A, -B, -DRB1) Presence of matched unrelated donor (10/10), available on time. Pregnancy or breast-feeding. Evidence of HIV infection or known HIV positive serology. Current uncontrolled bacterial, viral or fungal infection Evidence of progression of clinical symptoms or radiologic findings. Prior allogeneic hematopoietic stem cell transplant. Central Nervous System (CNS) lymphoma localization
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Luca Castagna, MD
Phone
+39028224
Ext
4587
Email
luca.castagna@humanitas.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Luca Castagna, MD
Organizational Affiliation
Istituto Clinico Humanitas
Official's Role
Principal Investigator
Facility Information:
Facility Name
Istituto Clinico Humanitas
City
Rozzano
State/Province
MI
ZIP/Postal Code
20089
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Luca Castagna, MD
Phone
+39028224
Ext
4587
Email
luca.castagna@humanitas.it
First Name & Middle Initial & Last Name & Degree
Luca Castagna, MD

12. IPD Sharing Statement

Citations:
PubMed Identifier
25742699
Citation
Roberto A, Castagna L, Zanon V, Bramanti S, Crocchiolo R, McLaren JE, Gandolfi S, Tentorio P, Sarina B, Timofeeva I, Santoro A, Carlo-Stella C, Bruno B, Carniti C, Corradini P, Gostick E, Ladell K, Price DA, Roederer M, Mavilio D, Lugli E. Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation. Blood. 2015 Apr 30;125(18):2855-64. doi: 10.1182/blood-2014-11-608406. Epub 2015 Mar 5.
Results Reference
derived

Learn more about this trial

Reduced Intensity Conditioning (RIC) Regimen and Post-transplant Cyclophosphamide in Haploidentical Bone Marrow Transplantation in in Patients With Poor Prognosis Lymphomas

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