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

May 9, 2016 updated by: Silvio Aime

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Novara, Italy, 28100
        • Dip. Scienze Mediche & IRCAD-Università, UDA Ematologia
      • Perugia, Italy, 06123
        • Policlinico Monteluce, Clinica Medica I
      • Reggio Calabria, Italy
        • Divisione Di Ematologia, Ospedali Riuniti
      • Reggio Emilia, Italy, 42100
        • Servizio di Ematologia, Azienda Ospedaliera S. Maria Nuova
    • TO
      • Torino, TO, Italy, 10126
        • Div. Univ. Di Ematologia, Az. Osp. San Giovanni Battista

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
7 months
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
7 months

Secondary Outcome Measures

Outcome Measure
Time Frame
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.
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.
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.
it will be evaluated from the date of enrolling until the date of first documented evidence of the end point.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Silvio Aime

Investigators

  • Principal Investigator: MARIO BOCCADORO, MD, DIVISIONE DI EMATOLOGIA DELL'UNIVERSITA' DI TORINO, AZIENDA OSPEDALIERA SAN GIOVANNI BATTISTA, TORINO, ITALY

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2006

Primary Completion (Actual)

September 1, 2010

Study Completion (Actual)

April 1, 2014

Study Registration Dates

First Submitted

November 30, 2006

First Submitted That Met QC Criteria

November 30, 2006

First Posted (Estimate)

December 4, 2006

Study Record Updates

Last Update Posted (Estimate)

May 10, 2016

Last Update Submitted That Met QC Criteria

May 9, 2016

Last Verified

May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MM2005

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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