We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is currently recruiting participants.
Verified November 2016 by Assistance Publique - Hôpitaux de Paris
Sponsor:
ClinicalTrials.gov Identifier:
NCT02333838
First Posted: January 7, 2015
Last Update Posted: November 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
  Purpose
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).

Condition Intervention Phase
Leukemia, Myeloid Drug: IV Thiotepa Drug: IV Fludarabine Drug: IV Busulfan Drug: IV Anti-thymocyte globuline Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Reduced Toxicity Conditioning Prior to Unrelated Cord Cell Transplantation for High Risk Myeloid Malignancies

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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

  • Incidence and severity of acute GVHD [ Time Frame: 6 months after transplantation ]
    Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)

  • 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 )

  • 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)

  • 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)


Estimated Enrollment: 57
Actual Study Start Date: May 2015
Estimated Study Completion Date: May 2019
Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)
Drug: IV Thiotepa
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 Name: Thiotepa
Drug: IV Fludarabine
IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)
Other Name: Fludarabine
Drug: IV Busulfan
(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 Name: Busulfan
Drug: IV Anti-thymocyte globuline
(Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)
Other Name: Anti-thymocyte globuline

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02333838


Contacts
Contact: Marie Thérèse RUBIO +333 83 15 46 21 m.rubio@chru-nancy.fr

Locations
France
Hôpital de Brabois, Hématologie Clinique et thérapie cellulaire Recruiting
Vandoeuvre les Nancy, France, 54511
Contact: Marie-Thérèse RUBIO    +333. 83.15.46.21    m.rubio@chru-nancy.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Marie Thérèse RUBIO CHRU Nancy
  More Information

Publications:

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02333838     History of Changes
Other Study ID Numbers: P130916
2014-002109-39 ( EudraCT Number )
First Submitted: December 19, 2014
First Posted: January 7, 2015
Last Update Posted: November 21, 2017
Last Verified: November 2016

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Cord Cell Transplantation
High risk myeloid malignancies

Additional relevant MeSH terms:
Neoplasms
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Fludarabine
Fludarabine phosphate
Busulfan
Thiotepa
Vidarabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Alkylating Agents
Antineoplastic Agents, Alkylating
Myeloablative Agonists