Melphalan, Prednisone, Thalidomide and Defibrotide in Relapsed Multiple Myeloma Patients

Multiple Myeloma Clinical Trial

— MPTD  

Official title:

A Phase I/II, Multi-Center, Open Label Study of Melphalan, Prednisone, Thalidomide and Defibrotide in Advanced and Refractory Multiple Myeloma Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00406978
• Other study ID #: MM2005
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: November 30, 2006
• Last updated: May 9, 2016
• Start date: February 2006
• Est. completion date: April 2014

Study information

• Verified date: May 2016
• Source: University of Turin, Italy
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the safety and the efficacy of the association of Melphalan/ Prednisone/Thalidomide/Defibrotide (MPTD) as salvage treatment in advanced and refractory myeloma patients. This association might further increase the response rate achieved by oral MPT regimen

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: April 2014
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Each patient must meet all of the following inclusion criteria to be enrolled in the study:

• Patient is of a legally consenting age as defined by local regulations.

• Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.

• Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

• Female patient is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) for the duration of the study.

• Patient was previously diagnosed with multiple myeloma based on standard criteria (see Section 13.2).

• Patient is relapsed after one line of treatment but less than three lines, including high-dose chemotherapy with stem cell support, conventional poli-chemotherapy, thalidomide- and melphalan-based regimens

• Patient with primary refractory disease will be considered not eligible

• Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein value (generally, but not necessarily, greater than 1 g/dL of IgG M-Protein and greater than 0.5 g/dL of IgA M-Protein) and, where applicable, urine light-chain excretion of >200 mg/24 hours.

• Patient has a Karnofsky performance status =60%.

• Patient has a life-expectancy >3 months.

• Patient has the following laboratory values within 14 days before Baseline (day 1 of the Cycle 1, before study drug administration):

• Platelet count =90 x 109/L without transfusion support within 7 days before the test.

• Absolute neutrophil count (ANC) = 1.00 x 109/L without the use of growth factors

• Corrected serum calcium =14 mg/dL (3.5 mmol/L).

• Aspartate transaminase (AST): = 2.5 x the upper limit of normal (ULN).

• Alanine transaminase (AST): = 2.5 x the ULN.

• Total bilirubin: = 1.5 x the ULN.

• Calculated or measured creatinine clearance: =20 mL/minute

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study.

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.

• Pregnant or beast feeding females.

• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

• Use of any other concomitant standard/experimental anti-myeloma drug or therapy

• Known positive for HIV or active infectious hepatitis, type B or C

• Other concurrent anticoagulation treatment

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Prednisone
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)
• Melphalan
Melphalan will be given orally at the dose of 0.25 mg/Kg for 4 days,
• 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.
• 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

Locations

Country	Name	City	State
Italy	Dip. Scienze Mediche & IRCAD-Università, UDA Ematologia	Novara
Italy	Policlinico Monteluce, Clinica Medica I	Perugia
Italy	Divisione Di Ematologia, Ospedali Riuniti	Reggio Calabria
Italy	Servizio di Ematologia, Azienda Ospedaliera S. Maria Nuova	Reggio Emilia
Italy	Div. Univ. Di Ematologia, Az. Osp. San Giovanni Battista	Torino	TO

Sponsors (1)

Lead Sponsor	Collaborator
Silvio Aime

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol. 1990 Feb;33(2):86-9. — View Citation

Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. — View Citation

Buzaid AC, Durie BG. Management of refractory myeloma: a review. J Clin Oncol. 1988 May;6(5):889-905. Review. — View Citation

McKean-Cowdin R, Feigelson HS, Ross RK, Pike MC, Henderson BE. Declining cancer rates in the 1990s. J Clin Oncol. 2000 Jun;18(11):2258-68. — View Citation

Palumbo A, Bertola A, Falco P, Rosato R, Cavallo F, Giaccone L, Bringhen S, Musto P, Pregno P, Caravita T, Ciccone G, Boccadoro M. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J. 2004;5(4):318-24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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).		7 months	Yes
Secondary	prolongation of progression-free survival		it will be evaluated from the date of enrolling until the date of first documented evidence of the end point.	Yes
Secondary	duration of progression-free survival		it will be evaluated from the date of enrolling until the date of first documented evidence of the end point.	Yes
Secondary	prolongs overall survival		it will be evaluated from the date of enrolling until the date of first documented evidence of the end point.	Yes