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

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 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.

Study Overview

• Status: Unknown
• Conditions: Lymphoma
• Intervention / Treatment: Drug: Thiotepa; Drug: Fludarabine; Drug: Cyclophosphamide

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.

• Study Type: Interventional
• Enrollment (Anticipated): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • MI
    • Rozzano, MI, Italy, 20089
      • Recruiting
      • Istituto Clinico Humanitas
      • Contact: Luca Castagna, MD; Phone Number: 4587 +39028224; Email: luca.castagna@humanitas.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: RIC regimen; Thiotepa, Fludarabine, Cyclophosphamide pre- and post- transplantation.

Drug: Thiotepa; Thiotepa (10 mg/kg /day) will be administered every 12 h, at day -6; Other Names: Tepadina; Drug: 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; Other Names: Fludara; Drug: 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).; Other Names: Endoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Incidence of graft failure		1 year
Cumulative incidence of acute and chronic GVHD		1 year
Incidence of infections	Possible infections will be monitored for a time period of 1 year post-transplantation and then if clinically required	1 year
Cumulative incidence of relapse/progression		1 year
Treatment related mortality (TRM)		1 year
Immunological reconstitution	T, B and NK subsets will be analysed in deep using cytofluorimetry and functional tests.	1 year

Collaborators and Investigators

• Sponsor: Istituto Clinico Humanitas

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (ANTICIPATED): August 1, 2016
• Study Completion (ANTICIPATED): November 1, 2016

Study Registration Dates

• First Submitted: January 28, 2014
• First Submitted That Met QC Criteria: January 29, 2014
• First Posted (ESTIMATE): January 30, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): January 30, 2014
• Last Update Submitted That Met QC Criteria: January 29, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Thiotepa
• Other Study ID Numbers: ONC-2011-005