Clinical trial NCT00598624: Clinical Trial to Evaluate the Safety and Efficacy of Treosulfan Based Conditioning Prior to Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)
Official title: Clinical Phase II Trial to Evaluate the Safety and Efficacy of Treosulfan Based Conditioning Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Patients With Haematological Malignancies
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Leukemia
Chronic Myeloid Leukemia
Myelodysplastic Syndrome
Diffuse Large Cell Lymphoma
Hodgkin Lymphoma
Chronic Lymphocytic Leukemia
Multiple Myeloma
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
First posted: 2008-01-22
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a multicentric, non-randomized, non-controlled open-label phase II trial to evaluate the safety and efficacy of treosulfan in a combination regimen with fludarabine as conditioning therapy prior to allogeneic stem cell transplantation (SCT) in patients with haematological malignancies.

The aim is to demonstrate a clinical benefit compared with historical data on intravenous busulfan (BusulfexTM, BusilvexTM), the only drug so far registered in the indication conditioning before allogeneic stem cell transplantation.


Eligibility criteria: Inclusion Criteria:

1. Patients with haematological malignancies, according to WHO classification, such as:

   * acute myeloid leukaemia -AML- in CR1 except "low-risk cases" defined by t(15;17), t(8;21), inv 16 or normal cytogenetics at diagnosis with FLT3-ITD negative and NPM-1 positive, with no high risk clinical criteria
   * any AML beyond CR1
   * acute lymphoblast leukaemia -ALL- in CR1 only if at "high risk" defined by cytogenetics as t(9;22), t(4;11) or for persistence of minimal residual disease (MRD)
   * any ALL beyond CR1
   * chronic myeloid leukaemia -CML- in chronic phase (CP) or accelerated phase (AP) intolerant/not responsive to TK-inhibitors
   * myeloproliferative disorders -MPD-
   * myelodysplastic syndrome -MDS- with intermediate or high risk International Prognostic Scoring System (IPSS)
   * diffuse large cell lymphoma -DLCL- with a chemosensitive relapse or beyond CR1
   * lymphoblastic and Burkitt lymphoma with a chemosensitive relapse or beyond CR1
   * mantle cell lymphoma -MCL- with a chemosensitive relapse or beyond CR1
   * follicular lymphoma -FCL- with a chemosensitive relapse or beyond CR2
   * Hodgkin lymphoma -HD- with a chemosensitive relapse or beyond CR1
   * chronic lymphocytic leukaemia -CLL- at "poor risk" in CR1 or with a chemosensitive relapse
   * CLL relapsing after high dose chemotherapy
   * T-cell non Hodgkin lymphoma -T-NHL- in CR1 or beyond
   * multiple myeloma -MM- at high risk for cytogenetics or ISS stage 3 in CR1 following high dose chemotherapy
   * MM at any relapse/progression except refractory disease
2. Availability of an HLA-identical sibling donor (MRD) or HLA-identical unrelated donor (MUD)

   * HLA-identity defined by the following markers: A, B, DRB1, DQB1 or a single or double Cord Blood unit (CB) with at least a 4 out of 6 HLA-matching by the following markers: A, B and DRB.

   A) identity between the 2 CB units and the recipient;

   B) Two identical CB units with one or two mismatches with the recipient;

   C) Two CB units with one mismatch between them and two mismatches with the recipient. We will prefer mismatches either for class I or for class II antigens; we will avoid mismatches concerning both classes I and II together.
3. Target graft size (unmanipulated, preferably not cryopreserved)

   * bone marrow: 2 to 10 x 106 CD34+ cells/kg BW recipient or \> 2 x 108 nucleated cells/kg BW recipient or
   * peripheral blood: 4 to 10 x 106 CD34+ cells/kg BW recipient
4. Age \> 18 and \< 70 years
5. Karnofsky Index \> 80 %
6. Adequate contraception in female patients of child-bearing potential
7. Written informed consent

Exclusion Criteria:

1. Secondary malignancies
2. Previous allogeneic transplantation
3. Hematopoietic cell transplantation-specific comorbidity index \> 4 (HCT-CI Sorror et al, Appendix M)
4. Known and manifested malignant involvement of the CNS
5. Active infectious disease
6. HIV- positivity or active hepatitis infection
7. Impaired liver function (Bilirubin \> upper normal limit; Transaminases \> 3.0 x upper normal limit)
8. Impaired renal function (Creatinine-clearance \< 60 ml/min; Serum Creatinine \> 1.5 x upper normal limit).
9. Pleural effusion or ascites \> 1.0 L
10. Pregnancy or lactation
11. Known hypersensitivity to treosulfan and/or fludarabine
12. Participation in another experimental drug trial within 4 weeks before day -6
13. Non-co-operative behaviour or non-compliance
14. Psychiatric diseases or conditions that might impair the ability to give informed consent

Primary outcomes:
measure: Efficacy: Evaluation of engraftment
timeFrame: 28 days
measure: Safety: Evaluation of the incidence of CTC grade 3 and 4 adverse events
timeFrame: between day -6 and day +28
Secondary outcomes:
measure: Efficacy: Evaluation of disease free survival (DFS)
timeFrame: 1 year
measure: Efficacy: Evaluation of overall survival (OS)
timeFrame: 1 year
measure: Efficacy: Evaluation of relapse incidence (RI)
timeFrame: 1 year
measure: Efficacy: Documentation of donor chimerism
timeFrame: on day +28, +56 and +100
measure: Safety: Evaluation of incidence of non-relapse mortality (NRM)
timeFrame: on day +28 and day +100
measure: Safety: cumulative incidence of NRM
timeFrame: 1 year
measure: Safety: Evaluation of cumulative incidence and severity of acute and chronic graft vs. host disease (GvHD)
timeFrame: 1 year
measure: Safety: EBV reactivation
timeFrame: 1 year
Other outcomes:
Locations:
city: San Giovanni Rotondo
country: Italy
facility: Ematologia, Ospedale Casa Sollievo della Sofferenza
state: Foggia
city: Milano
country: Italy
facility: IRCCS San Raffaele; Unità Operativa di Ematologia
state: MI
city: Bergamo
country: Italy
facility: USC Ematologia, Ospedali Riuniti
city: Bolzano
country: Italy
facility: Ospedale centrale di Bolzano - Reparto di Ematologia
city: Cagliari
country: Italy
facility: PO "R.Binaghi" - CTMO
city: Cuneo
country: Italy
facility: AO "Santa Croce" e Carle - Reparto di Ematologia
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia - Divisione di Ematologia
city: Pescara
country: Italy
facility: Ospedale Civile - UTI ematologia per il trapianto emopoietico
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova - SC di Ematologia
city: Roma
country: Italy
facility: Dipartimento Biotecnologie Cellulari ed Ematologia; Azienda Policlinico Umberto I
city: Roma
country: Italy
facility: AO San Camillo Forlanini - UOC ematologia e trapianto
city: Udine
country: Italy
facility: AOU Santa Maria della Misericordia - Clinica Ematologica
Study officials:
name: Fabio FC Ciceri, MD
role: STUDY_DIRECTOR
References:
citation: Lazzari L, Ruggeri A, Lupo Stanghellini MT, Mastaglio S, Messina C, Giglio F, Lorusso A, Perini T, Piemontese S, Marcatti M, Lorentino F, Xue E, Clerici D, Corti C, Bernardi M, Assanelli A, Greco R, Ciceri F, Peccatori J. Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial. Front Oncol. 2021 Sep 10;11:731478. doi: 10.3389/fonc.2021.731478. eCollection 2021.