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Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies (TBF-Cord)

Primary Purpose

Leukemia, Myeloid

Status
Unknown status
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
IV Thiotepa
IV Fludarabine
IV Busulfan
IV Anti-thymocyte globuline
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Leukemia, Myeloid focused on measuring Cord Cell Transplantation, High risk myeloid malignancies

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥18 years and ≤ 65 years
  • Patients diagnosed with one of the following diseases (validation of the indication of allogeneic

HSCT with an alternative source of hematopoietic stem cells by centers' local RCP):

  • Acute myelogenous leukemia (AML) with intermediate or high risk features ((≥ intermediate risk 1) in CR1 or above according to centers' decision
  • Myelodysplastic syndromes with International Prognostic Scoring System (IPSS) score ³ 2 (cf. appendix 3) or with symptomatic pancytopenia according to centers' decision
  • Chronic myelomonocytic leukemia (CMML)
  • Both MDS and CMML should have ≤ 10% blasts at transplantation
  • Absence of a matched sibling or unrelated donor (10/10 or 9/10 if mismatch on HLA Cw, based on each center's donor selection criteria)
  • Cord blood units must be matched with patient at 4, 5, or 6/6 HLA loci, (class I antigenic & class II allelic level)with a minimum of 3.5 x 10^7 TNC/kg recipient body weight in the pre-thawed fraction and with ≥2.5x10^7 TNC/kg for the richest cord blood unit and ≥ 1.5x10^7 TNC/kg for the poorest blood unit in case of 2 cord blood units
  • Performance status : OMS score ≤ 1 (cf. appendix 5)
  • Cardiac function - left ventricular ejection fraction ≥ 45%.
  • Pulmonary function - diffusion capacity of at least 50% predicted.
  • Serum creatinine clearance 0 ml/min.
  • SGPT 4x normal , serum bilirubin < 2 x normal.
  • Written informed consent.
  • Progestative treatment for women with persisting menstrual periods

Exclusion Criteria:

  • Presence of a matched sibling or unrelated available donor (10/10 or 9/10 if mismatch on HLA Cw in centers performing 9/10 HLA mismatched transplants)
  • Active infection at time of conditioning. In case of uncertainty regarding whether a previous infection is resolved or not, this will be discussed with the PI on a case by case basis.
  • Pregnancy in women with child bearing potential (pregnancy test performed within 2-4 weeks of study entry).
  • HIV positive
  • Active CNS leukemia
  • Chronic or active Hepatitis B or Hepatitis C. If questions about liver health discuss with PI and strongly consider liver biopsy.
  • Poor performance status : OMS score > 1
  • Life expectancy is severely limited by concomitant illness and expected to be <12 weeks.
  • Left ventricular ejection fraction <45%. Uncontrolled arrhythmias or symptomatic cardiac disease.
  • Symptomatic pulmonary disease. FEV1, FVC and DLCO <50% of expected corrected for hemoglobin.
  • Serum creatinine clearance (Crockoft) below 50 mL/m per 1.73 m² or requiring dialysis
  • Vaccination with alive vaccine (virus or bacteria) < 3 months
  • Fludarabine contra-indication
  • Thymoglobuline contra-indication
  • Patient under guardianship or curatorship

Sites / Locations

  • Hôpital de Brabois, Hématologie Clinique et thérapie cellulaire

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Reduced toxicity conditioning regimen

Arm Description

Reduced toxicity conditioning regimen (thiotepa, busulfan, fludarabine and ATG) followed by unrelated cord blood allogeneic stem cell transplant for high risk myeloïd malignancies. The conditioning regimen will include: IV Thiotepa (5 mg/Kg/day for 2 days) (Day -7 and -6) IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2) IV Busulfan (Busilvex 130 mg/m2/day for 3 days) (Day-5, -4 and -3) IV Anti-thymocyte globuline (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2) In patient with co-morbidities and/or older than 60 years, conditioning could be reduced after consulting the coordinator of the study: IV Thiotepa (5 mg/Kg/day for 2 days) (Day -6) IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2) IV Busulfan (Busilvex 100 mg/m2/day for 3 days) (Day-5, -4 and -3) IV Anti-thymocyte globuline (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)

Outcomes

Primary Outcome Measures

Cumulative incidence of NRM at 12 months after transplantation
Cumulative incidence of NRM at 12 months after transplantation : Safety and efficacy of the pre-transplant reduced toxicity conditioning regimen

Secondary Outcome Measures

Incidence of engraftment after transplantation
Incidence of neutrophil engraftment (day and proportion of patients reaching neutrophils >0.5x109/L); and platelets recovery (day and proportion of patients reaching platelets > 20 x 109 / L without transfusion) after transplantation
Incidence and severity of acute GVHD
Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)
Incidence and severity of chronic GVHD
Incidence and severity of chronic GVHD (diagnosed and graded as standard criteria detailed )
Rate of disease relapse at one year after transplantation
Incidence of disease relapse at one year after transplantation (relapse is defined on the basis of morphologica evidence of leukemic cells in the bone marrow or other sites)
Quality of life
Evaluation of the quality of life (using a french translation of the FACT-BMT (version 4.0)

Full Information

First Posted
December 19, 2014
Last Updated
August 10, 2018
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT02333838
Brief Title
Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies
Acronym
TBF-Cord
Official Title
Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Unknown status
Study Start Date
May 2015 (Actual)
Primary Completion Date
May 2018 (Actual)
Study Completion Date
May 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Allogeneic cord blood stem cell transplantation is a potentially curative therapy for patients with haematological malignancies. We have extensive experience with the use of Cord Blood Transplantation (CBT) in patients with advanced myeloid malignancies. In adults however, the 40% Non-Relapse Mortality (NRM) rate observed after CBT conditioned with a myeloablative conditioning has encouraged the development of CBT with Reduced Intensity Conditioning (RIC). Our previous national CBT protocol (the Minicord French protocol - NCT00797758) showed that RIC CBT can reduce NRM, but relapse remains the main post-transplant event (>30% at one year). Thus, the development of reduced toxicity rather than RIC conditioning for CBT is warranted in order to improve the outcome of such transplants by limiting NRM and reducing relapse rate. The Fludarabine, ATG and intensified doses of IV Busulfan (9.6 mg/Kg total dose) regimen is a well-established preparative regimen for reduced-intensity/toxicity conditioning prior to allogeneic stem cell transplantation using peripheral blood stem cells mobilized with G-CSF (ClinicalTrials.gov Identifier: NCT00841724). However, such regimen is likely not sufficient to allow for CB cell engraftment. Thiotepa is an alkylating and radio-mimetic agent with a large anti-tumor activity including leukemic cells, the ability to cross the blood-brain barrier and to improve engraftment of hematopoietic stem cells. This drug has been combined to usual conditioning regimen without increasing the toxicity but improving the engraftment rate and potentially reducing the relapse rate. Thus, in the context of adult CBT for high risk myeloid malignancies, we propose to prospectively evaluate a reduced toxicity conditioning based on the association of Thiotepa, Fludarabine, IV Busulfan and ATG with the objective to achieve acceptable NRM rates, and to allow for improved anti-leukemic control based on the cytotoxic component of the conditioning regimen itself, while waiting for the long term immune-mediated disease control (GVL effect).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid
Keywords
Cord Cell Transplantation, High risk myeloid malignancies

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Reduced toxicity conditioning regimen
Arm Type
Experimental
Arm Description
Reduced toxicity conditioning regimen (thiotepa, busulfan, fludarabine and ATG) followed by unrelated cord blood allogeneic stem cell transplant for high risk myeloïd malignancies. The conditioning regimen will include: IV Thiotepa (5 mg/Kg/day for 2 days) (Day -7 and -6) IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2) IV Busulfan (Busilvex 130 mg/m2/day for 3 days) (Day-5, -4 and -3) IV Anti-thymocyte globuline (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2) In patient with co-morbidities and/or older than 60 years, conditioning could be reduced after consulting the coordinator of the study: IV Thiotepa (5 mg/Kg/day for 2 days) (Day -6) IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2) IV Busulfan (Busilvex 100 mg/m2/day for 3 days) (Day-5, -4 and -3) IV Anti-thymocyte globuline (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)
Intervention Type
Drug
Intervention Name(s)
IV Thiotepa
Other Intervention Name(s)
Thiotepa
Intervention Description
IV Thiotepa (5 mg/Kg/day for 2 days) (Day -7 and -6) or IV Thiotepa (5 mg/Kg/day for 2 days) (Day -6)
Intervention Type
Drug
Intervention Name(s)
IV Fludarabine
Other Intervention Name(s)
Fludarabine
Intervention Description
IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)
Intervention Type
Drug
Intervention Name(s)
IV Busulfan
Other Intervention Name(s)
Busulfan
Intervention Description
(Busilvex 130 mg/m2/day for 3 days) (Day-5, -4 and -3) or (Busilvex 100 mg/m2/day for 3 days) (Day-5, -4 and -3)
Intervention Type
Drug
Intervention Name(s)
IV Anti-thymocyte globuline
Other Intervention Name(s)
Anti-thymocyte globuline
Intervention Description
(Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)
Primary Outcome Measure Information:
Title
Cumulative incidence of NRM at 12 months after transplantation
Description
Cumulative incidence of NRM at 12 months after transplantation : Safety and efficacy of the pre-transplant reduced toxicity conditioning regimen
Time Frame
12 months after transplantation
Secondary Outcome Measure Information:
Title
Incidence of engraftment after transplantation
Description
Incidence of neutrophil engraftment (day and proportion of patients reaching neutrophils >0.5x109/L); and platelets recovery (day and proportion of patients reaching platelets > 20 x 109 / L without transfusion) after transplantation
Time Frame
12 months after transplantation
Title
Incidence and severity of acute GVHD
Description
Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)
Time Frame
6 months after transplantation
Title
Incidence and severity of chronic GVHD
Description
Incidence and severity of chronic GVHD (diagnosed and graded as standard criteria detailed )
Time Frame
12 months after transplantation
Title
Rate of disease relapse at one year after transplantation
Description
Incidence of disease relapse at one year after transplantation (relapse is defined on the basis of morphologica evidence of leukemic cells in the bone marrow or other sites)
Time Frame
12 months after transplantation
Title
Quality of life
Description
Evaluation of the quality of life (using a french translation of the FACT-BMT (version 4.0)
Time Frame
12 months after transplantation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥18 years and ≤ 65 years Patients diagnosed with one of the following diseases (validation of the indication of allogeneic HSCT with an alternative source of hematopoietic stem cells by centers' local RCP): Acute myelogenous leukemia (AML) with intermediate or high risk features ((≥ intermediate risk 1) in CR1 or above according to centers' decision Myelodysplastic syndromes with International Prognostic Scoring System (IPSS) score ³ 2 (cf. appendix 3) or with symptomatic pancytopenia according to centers' decision Chronic myelomonocytic leukemia (CMML) Both MDS and CMML should have ≤ 10% blasts at transplantation Absence of a matched sibling or unrelated donor (10/10 or 9/10 if mismatch on HLA Cw, based on each center's donor selection criteria) Cord blood units must be matched with patient at 4, 5, or 6/6 HLA loci, (class I antigenic & class II allelic level)with a minimum of 3.5 x 10^7 TNC/kg recipient body weight in the pre-thawed fraction and with ≥2.5x10^7 TNC/kg for the richest cord blood unit and ≥ 1.5x10^7 TNC/kg for the poorest blood unit in case of 2 cord blood units Performance status : OMS score ≤ 1 (cf. appendix 5) Cardiac function - left ventricular ejection fraction ≥ 45%. Pulmonary function - diffusion capacity of at least 50% predicted. Serum creatinine clearance 0 ml/min. SGPT 4x normal , serum bilirubin < 2 x normal. Written informed consent. Progestative treatment for women with persisting menstrual periods Exclusion Criteria: Presence of a matched sibling or unrelated available donor (10/10 or 9/10 if mismatch on HLA Cw in centers performing 9/10 HLA mismatched transplants) Active infection at time of conditioning. In case of uncertainty regarding whether a previous infection is resolved or not, this will be discussed with the PI on a case by case basis. Pregnancy in women with child bearing potential (pregnancy test performed within 2-4 weeks of study entry). HIV positive Active CNS leukemia Chronic or active Hepatitis B or Hepatitis C. If questions about liver health discuss with PI and strongly consider liver biopsy. Poor performance status : OMS score > 1 Life expectancy is severely limited by concomitant illness and expected to be <12 weeks. Left ventricular ejection fraction <45%. Uncontrolled arrhythmias or symptomatic cardiac disease. Symptomatic pulmonary disease. FEV1, FVC and DLCO <50% of expected corrected for hemoglobin. Serum creatinine clearance (Crockoft) below 50 mL/m per 1.73 m² or requiring dialysis Vaccination with alive vaccine (virus or bacteria) < 3 months Fludarabine contra-indication Thymoglobuline contra-indication Patient under guardianship or curatorship
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marie Thérèse RUBIO
Organizational Affiliation
CHRU Nancy
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital de Brabois, Hématologie Clinique et thérapie cellulaire
City
Vandoeuvre les Nancy
ZIP/Postal Code
54511
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
15564544
Citation
Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, Jacobsen N, Ruutu T, de Lima M, Finke J, Frassoni F, Gluckman E; Acute Leukemia Working Party of European Blood and Marrow Transplant Group; Eurocord-Netcord Registry. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004 Nov 25;351(22):2276-85. doi: 10.1056/NEJMoa041469.
Results Reference
background
PubMed Identifier
16461307
Citation
Arcese W, Rocha V, Labopin M, Sanz G, Iori AP, de Lima M, Sirvent A, Busca A, Asano S, Ionescu I, Wernet P, Gluckman E; Eurocord-Netcord Transplant group. Unrelated cord blood transplants in adults with hematologic malignancies. Haematologica. 2006 Feb;91(2):223-30.
Results Reference
background
PubMed Identifier
19104080
Citation
Atsuta Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, Kai S, Sakamaki H, Kouzai Y, Kasai M, Fukuda T, Azuma H, Takanashi M, Okamoto S, Tsuchida M, Kawa K, Morishima Y, Kodera Y, Kato S; Japan Cord Blood Bank Network. Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia. Blood. 2009 Feb 19;113(8):1631-8. doi: 10.1182/blood-2008-03-147041. Epub 2008 Dec 22.
Results Reference
background
PubMed Identifier
20558104
Citation
Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, Sirvent A, Champlin RE, Chao N, Gee AP, Isola L, Laughlin MJ, Marks DI, Nabhan S, Ruggeri A, Soiffer R, Horowitz MM, Gluckman E, Wagner JE; Center for International Blood and Marrow Transplant Research; Acute Leukemia Working Party Eurocord (the European Group for Blood Marrow Transplantation); National Cord Blood Program of the New York Blood Center. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010 Jul;11(7):653-60. doi: 10.1016/S1470-2045(10)70127-3.
Results Reference
background

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Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies

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