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Leukemia, MyeloidPhase 2TBF-CordNCT02333838

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

A Phase 2 study testing IV Thiotepa, IV Fludarabine and IV Busulfan in people with Leukemia, Myeloid, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Leukemia, Myeloid
What is being tested?
IV Thiotepa, IV Fludarabine and IV Busulfan
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
1 siteFrance
Study dates
May 2015to May 2019
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

1 site in 1 country.

France1 site
  • Hôpital de Brabois, Hématologie Clinique et thérapie cellulaire

    Vandœuvre-lès-Nancy, 54511

Other trials in France

About this study

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).

Being tested
IV Thiotepa, IV Fludarabine, IV Busulfan, IV Anti-thymocyte globuline
Keywords
Cord Cell Transplantation, High risk myeloid malignancies
Medical subject headings
Leukemia, Myeloid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IV ThiotepaDrug

    Also called 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)

  • IV FludarabineDrug

    Also called Fludarabine

    IV fludarabine (40 mg/m²/day for 4 days) (from Day-5 to day -2)

  • IV BusulfanDrug

    Also called 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)

  • IV Anti-thymocyte globulineDrug

    Also called Anti-thymocyte globuline

    (Thymogobuline®, 2.5 mg/kg/day for 2 days) (Day-3 and -2)

Study groups in NCT02333838
Study groupRoleWhat they receive
Reduced toxicity conditioning regimenExperimentalReduced 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)
Receives: Drug: IV Thiotepa; Drug: IV Fludarabine; Drug: IV Busulfan; Drug: IV Anti-thymocyte globuline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 12 months after transplantation

Secondary outcomes (5)
  1. 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

    Measured: 12 months after transplantation

  2. Incidence and severity of acute GVHD

    Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)

    Measured: 6 months after transplantation

  3. Incidence and severity of chronic GVHD

    Incidence and severity of chronic GVHD (diagnosed and graded as standard criteria detailed )

    Measured: 12 months after transplantation

  4. 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)

    Measured: 12 months after transplantation

  5. Quality of life

    Evaluation of the quality of life (using a french translation of the FACT-BMT (version 4.0)

    Measured: 12 months after transplantation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Jan 2015 (estimated)
  2. Study startMay 2015
  3. Primary completionMay 2018
  4. Study completionMay 2019 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Other
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02333838
Sponsor's protocol ID
P130916
Other IDs
2014-002109-39, 2014
Acronym
TBF-Cord
Status last verified
Jul 2018
First submitted
19 Dec 2014
Last updated
13 Aug 2018
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 15564544
  • 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.

    PubMed 16461307
  • 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.

    PubMed 19104080
  • 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.

    PubMed 20558104

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing IV Thiotepa, IV Fludarabine and IV Busulfan in people with Leukemia, Myeloid, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 13 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cumulative incidence of NRM at 12 months after transplantation (time frame: 12 months after transplantation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02333838, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2018.

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