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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Unknown status

CT.gov ID

NCT02333838

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

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).

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

Study Design

Study Type:

Interventional

Actual Enrollment :

31 participants

Allocation:

N/A

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

Actual Study Start Date :

May 1, 2015

Actual Primary Completion Date :

May 1, 2018

Anticipated Study Completion Date :

May 1, 2019

Arms and Interventions

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

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)

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 Names:

Thiotepa

Drug: IV Fludarabine

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

Other Names:

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 Names:

Busulfan

Drug: IV Anti-thymocyte globuline

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

Other Names:

Anti-thymocyte globuline

Outcome Measures

Primary Outcome Measures

Cumulative incidence of NRM at 12 months after transplantation [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 [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 [6 months after transplantation]
Incidence and severity of acute GVHD (diagnosed and graded as standard criteria)
Incidence and severity of chronic GVHD [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 [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 [12 months after transplantation]
Evaluation of the quality of life (using a french translation of the FACT-BMT (version 4.0)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts 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