Melphalan, Prednisone, Thalidomide and Defibrotide in Relapsed Multiple Myeloma Patients (MPTD)

This study has been terminated.
(difficulties in enrolling patients)
Sponsor:
Information provided by:
University of Turin, Italy
ClinicalTrials.gov Identifier:
NCT00406978
First received: November 30, 2006
Last updated: October 18, 2010
Last verified: September 2010
  Purpose

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


Condition Intervention Phase
Multiple Myeloma
Drug: Prednisone
Drug: Melphalan
Drug: Thalidomide
Drug: Defibrotide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
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

Resource links provided by NLM:


Further study details as provided by University of Turin, Italy:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]
  • 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. ] [ Designated as safety issue: Yes ]
  • 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. ] [ Designated as safety issue: Yes ]

Enrollment: 24
Study Start Date: February 2006
Study Completion Date: September 2010
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MPTD 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)
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

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00406978

Locations
Italy
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
Sponsors and Collaborators
University of Turin, Italy
Investigators
Principal Investigator: MARIO BOCCADORO, MD DIVISIONE DI EMATOLOGIA DELL'UNIVERSITA' DI TORINO, AZIENDA OSPEDALIERA SAN GIOVANNI BATTISTA, TORINO, ITALY
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prof. Mario Boccadoro, Università di Torino
ClinicalTrials.gov Identifier: NCT00406978     History of Changes
Other Study ID Numbers: MM2005
Study First Received: November 30, 2006
Last Updated: October 18, 2010
Health Authority: Italy: Ministry of Health

Keywords provided by University of Turin, Italy:
MYELOMA
THALIDOMIDE
DEFIBRODITE

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Melphalan
Prednisone
Thalidomide
Defibrotide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Inflammatory Agents
Glucocorticoids

ClinicalTrials.gov processed this record on August 28, 2014