A Phase I/II, Multi-Center, Open Label Study of Melphalan, Prednisone, Thalidomide and Defibrotide in Advanced and Refractory Multiple Myeloma Patients
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.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The safety will be assessed by showing DLT and maximum tolerated dose (MTD) of defibrotide when administered in combination with MPT
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
7 months
Yes
MARIO BOCCADORO, MD
Principal Investigator
DIVISIONE DI EMATOLOGIA DELL'UNIVERSITA' DI TORINO, AZIENDA OSPEDALIERA SAN GIOVANNI BATTISTA, TORINO, ITALY
Italy: Ministry of Health
MM2005
NCT00406978
February 2006
September 2010
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