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

August 10, 2018 updated by: Assistance Publique - Hôpitaux de Paris
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).

Study Overview

Study Type

Interventional

Enrollment (Actual)

31

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Vandoeuvre les Nancy, France, 54511
        • Hôpital de Brabois, Hématologie Clinique et thérapie cellulaire

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Reduced toxicity conditioning regimen

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)
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)
Other Names:
  • Thiotepa
IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)
Other Names:
  • Fludarabine
(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)
Other Names:
  • Busulfan
(Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)
Other Names:
  • Anti-thymocyte globuline

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of engraftment after transplantation
Time Frame: 12 months 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
12 months after transplantation
Incidence and severity of acute GVHD
Time Frame: 6 months after transplantation
Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)
6 months after transplantation
Incidence and severity of chronic GVHD
Time Frame: 12 months after transplantation
Incidence and severity of chronic GVHD (diagnosed and graded as standard criteria detailed )
12 months after transplantation
Rate of disease relapse at one year after transplantation
Time Frame: 12 months 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)
12 months after transplantation
Quality of life
Time Frame: 12 months after transplantation
Evaluation of the quality of life (using a french translation of the FACT-BMT (version 4.0)
12 months after transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Marie Thérèse RUBIO, CHRU Nancy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 1, 2015

Primary Completion (ACTUAL)

May 1, 2018

Study Completion (ANTICIPATED)

May 1, 2019

Study Registration Dates

First Submitted

December 19, 2014

First Submitted That Met QC Criteria

January 5, 2015

First Posted (ESTIMATE)

January 7, 2015

Study Record Updates

Last Update Posted (ACTUAL)

August 13, 2018

Last Update Submitted That Met QC Criteria

August 10, 2018

Last Verified

July 1, 2018

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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