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

Phase 1/Phase 2
18 Years
Not Enrolling
Multiple Myeloma

Thank you

Trial Information

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

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.

Inclusion Criteria:

- Each patient must meet all of the following inclusion criteria to be enrolled in the

- 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consent may be withdrawn by the patient at any time without prejudice to their future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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

The safety will be assessed by showing DLT and maximum tolerated dose (MTD) of defibrotide when administered in combination with MPT

Outcome Description:

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

Outcome Time Frame:

7 months

Safety Issue:


Principal Investigator


Investigator Role:

Principal Investigator

Investigator Affiliation:



Italy: Ministry of Health

Study ID:




Start Date:

February 2006

Completion Date:

September 2010

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell