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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02049580
• Other study ID #: ONC-2011-005
• Status: Recruiting
• Phase: Phase 2
• First received: January 28, 2014
• Last updated: January 29, 2014
• Start date: July 2013
• Est. completion date: November 2016

Study information

• Verified date: January 2014
• Source: Istituto Clinico Humanitas
• Contact: Luca Castagna, MD
• Phone: +39028224
• Email: luca.castagna[@]humanitas.it
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 47
• Est. completion date: November 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

• 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

Study Design

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

Related Conditions & MeSH terms

• Lymphoma

Intervention

Drug:
• Thiotepa
Thiotepa (10 mg/kg /day) will be administered every 12 h, at day -6
• Fludarabine
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
• Cyclophosphamide
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).

Locations

Country	Name	City	State
Italy	Istituto Clinico Humanitas	Rozzano	MI

Sponsors (1)

Lead Sponsor	Collaborator
Istituto Clinico Humanitas

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	1 year	No
Secondary	Neutrophils recovery	Neutrophils will be measured at different time points of increasing lenght up to 1 year after transplant and then if clinically indicated	1 year	Yes
Secondary	Platelets recovery	Platelets will be measured at different time points of increasing lenght up to 1 year after transplant and then if clinically indicated	1 year	Yes
Secondary	Incidence of graft failure		1 year	Yes
Secondary	Cumulative incidence of acute and chronic GVHD		1 year	Yes
Secondary	Incidence of infections	Possible infections will be monitored for a time period of 1 year post-transplantation and then if clinically required	1 year	Yes
Secondary	Cumulative incidence of relapse/progression		1 year	No
Secondary	Treatment related mortality (TRM)		1 year	Yes
Secondary	Immunological reconstitution	T, B and NK subsets will be analysed in deep using cytofluorimetry and functional tests.	1 year	No