Melphalan, Prednisone, Thalidomide and Defibrotide in Relapsed Multiple Myeloma Patients (MPTD)
|Multiple Myeloma||Drug: Prednisone Drug: Melphalan Drug: Thalidomide Drug: Defibrotide||Phase 1 Phase 2|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II, Multi-Center, Open Label Study of Melphalan, Prednisone, Thalidomide and Defibrotide in Advanced and Refractory Multiple Myeloma Patients|
- The safety will be assessed by showing DLT and maximum tolerated dose (MTD) of defibrotide when administered in combination with MPT [ Time Frame: 7 months ]
The DLT is defined by the development of febrile neutropenia, or Grade 4 neutropenia >= a week, or Grade 4 hematologic toxicity except neutropenia, or any >= Grade 3 non-hematologic toxicity considered by investigators to be related to study drug(s) in >30% of pts.
MTD: maximum tolerated dose
- The efficacy will be assessed by showing at least 55% of patients in a minimal response (MR) or at least 10 % of pts in near complete remission (nCR). [ Time Frame: 7 months ]
- prolongation of progression-free survival [ Time Frame: it will be evaluated from the date of enrolling until the date of first documented evidence of the end point. ]
- duration of progression-free survival [ Time Frame: it will be evaluated from the date of enrolling until the date of first documented evidence of the end point. ]
- prolongs overall survival [ Time Frame: it will be evaluated from the date of enrolling until the date of first documented evidence of the end point. ]
|Study Start Date:||February 2006|
|Study Completion Date:||April 2014|
|Primary Completion Date:||September 2010 (Final data collection date for primary outcome measure)|
Prednisone will be given orally at the dose of 1.5 mg/Kg for 4 days followed by a 31-day rest period (days 5 through 35)Drug: Melphalan
Melphalan will be given orally at the dose of 0.25 mg/Kg for 4 days,Drug: Thalidomide
Thalidomide will be administered orally at the initial dose of 50 mg/day p.o. once daily, with increment of 50 mg after a month to acceptable tolerance (maximum 100 mg), continuously for the entire 6 courses.Drug: Defibrotide
Lev - 1 Def = 10 mg/Kg (max 0.6 g) on days 1-4, followed by 1.2 g (400 mg every 8 hours) p.o. through day 35 Lev - 1 Def = 1.2 g p.o (400 mg every 8 hours) on days 1-4, followed by 1.2 g (400 mg every 8 hours) p.o. through day 35 Level + 1 Def = 17 mg/Kg (max 1.2 g) on days 1-4, followed by 1.6 g p.o. (400 mg every 6 hours) through day 35 Lev + 1 Def = 2.4 g p.o. (400 mg every 4 hours) on days 1-4, followed by 1.6 g p.o. (400 mg every 6 hours) through day 35 Lev + 2 Def = 34 mg/Kg (max 2.4 g) as a i.v. injection on days 1-4, followed by 3.2 g p.o. (800 mg every 6 hours) through day 35 Lev + 2 Def = 4.8 g p.o. (800 mg every 4 hours) on days 1-4, followed by 3.2 g p.o. (800 mg every 6 hours) through day 35 Lev + 3 Def = 51mg/Kg (max 3.6 g) as a i.v. injection on days 1-4, followed by 4.8 g p.o. (1200 mg every 6 hours) through day 35 Lev + 3 Def = 7.2 g p.o.(1200 mg every 4 hours ) on days 1-4, followed by 4.8 g p.o. (1200 mg every 6 hours) given p.o. through day 35
Defibrotide (DF) is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects, which has been shown to be active in various microangiopathies, including the treatment and prophylaxis of veno-occlusive disease. While DF has minimal inhibitory effect on multiple myeloma (MM) in cell isolates, it showed single agent activity on human MM xenografts in SCID/NOD mice and markedly increased responsiveness of MM to cytotoxic agents, including melphalan, cyclophosphamide and dexamethasone in the same models. DF might thus enhance the response rate of Melphalan, Prednisone and Thalidomide, while protecting against the prothrombotic state seen with this combination in the treatment of MM. In this multicenter, open label, non-randomised phase I/II trial, dosing safety and efficacy of melphalan, prednisone, thalidomide, and DF (MPTD) were determined in pts with relapsed/refractory MM.
Primary refractory or pts receiving therapeutic anticoagulation were excluded. Oral melphalan was administered at 0,25 mg/Kg on D1-4, oral prednisone at 1,5 mg/kg on D 1-4, thalidomide was delivered at 50 mg on D1-35 on cycle 1 and at 100 mg from cycle 2 to cycle 6.
Level + 1 DF = 17 mg/Kg i.v. or 2.4 g p.o. D1-4, followed by 1.6 g p.o. through D 35 Level + 2 DF = 34 mg/Kg i.v. or 4.8 g p.o. D 1-4, followed by 3.2 g p.o. through D 35 Level + 3 DF = 51 mg/Kg i.v. or 7.2 g p.o. D 1-4, followed by 4.8 g p.o. through D 35.
Each course was repeated every 35d for a total of 6 courses and no DVT prophylaxis was used.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00406978
|Div. Univ. Di Ematologia, Az. Osp. San Giovanni Battista|
|Torino, TO, Italy, 10126|
|Dip. Scienze Mediche & IRCAD-Università, UDA Ematologia|
|Novara, Italy, 28100|
|Policlinico Monteluce, Clinica Medica I|
|Perugia, Italy, 06123|
|Divisione Di Ematologia, Ospedali Riuniti|
|Reggio Calabria, Italy|
|Servizio di Ematologia, Azienda Ospedaliera S. Maria Nuova|
|Reggio Emilia, Italy, 42100|
|Principal Investigator:||MARIO BOCCADORO, MD||DIVISIONE DI EMATOLOGIA DELL'UNIVERSITA' DI TORINO, AZIENDA OSPEDALIERA SAN GIOVANNI BATTISTA, TORINO, ITALY|