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A Multicenter, Open-label, Phase Ii Study of Dasatinib in Combination With Melphalan and Prednisone (D-MP) in Advanced, Relapsed / Refractory Multiple Myeloma Patients

Phase 2
18 Years
75 Years
Not Enrolling

Thank you

Trial Information

A Multicenter, Open-label, Phase Ii Study of Dasatinib in Combination With Melphalan and Prednisone (D-MP) in Advanced, Relapsed / Refractory Multiple Myeloma Patients

Primary Objective: To determine whether the combination of dasatinib with melphalan and
prednisone provides therapeutic benefits and is safe in patients with relapsed/refractory
Multiple Myeloma.

Study design, dose and mode of administration, and duration of treatment: Multicenter,
open-label, single arm, two-stage, Phase II study of dasatinib in combination with melphalan
and prednisone (D-MP) in advanced, refractory MM patients. The three drugs will be
concurrently administered through 6 cycles; each cycle will be 28 days long (1 cycle = 4
weeks), for a total of 24 weeks of treatment. The treatment schedule will be the following:

- Melphalan 0,18 mg/Kg/day from day 1 to day 4 for 6 cycles;

- Prednisone 1,5 mg/Kg/day from day 1 to day 4 for 6 cycles;

- Dasatinib 100 mg QD continuously (from day 1 to day 28). After the 6 cycles of D-MP
treatment, Dasatinib will be continuously administered alone as maintenance, until
occurrence of progressive disease, unacceptable toxicity or informed consent

This is a two-stage Phase II trial according to Simon with a bivariate endpoint design, by
which treatment efficacy and safety are jointly evaluated. This design allows the trial to
be early stopped after the first stage if the number of observed partial responses (PR) is
inadequate and the number of observed toxicities is too high. In the first stage of the
protocol 17 patients are required.

Inclusion Criteria:

1. Age ≥ 18 years and ≤75 year

2. Karnofsky performance status ≥ 60%

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

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consent may be withdrawn by the patient at any time without prejudice to their future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

5. Patient of reproductive potential must agree to use and utilize an adequate method of
contraception throughout treatment and for at least 4 weeks after study drug is

6. Patient was previously diagnosed with symptomatic MM based on standard criteria, and
has measurable disease, defined as follows:

- Secretory myeloma: 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;

- Non-secretory myeloma: > 30% plasma cells in the bone marrow and at least one
plasmocytoma > 2 cm as determined by clinical examination or applicable
radiographs (i.e., MRI or CT scan).

7. Patient is relapsed or refractory and has received previous regimen containing
Thalidomide or Lenalidomide and Bortezomib or even MP (patient is refractory if there
is a progression during the last therapy or within 2 months after its completion).

8. Patient has a life-expectancy > 3 months

9. Patient has ≤ Grade 2 peripheral neuropathy within 28 days before enrollment and all
acute toxicities from any prior therapy (radiotherapy, chemotherapy or surgical
procedures) must have resolved to grade ≤ 2, according to the NCI CTCAE version 3.0
at study entry.

10. Patient has the ability to take oral medication (dasatinib must be swallowed whole)

11. Concomitant Medications:

- Patient agrees that IV bisphophonates will be withheld for the first 8 weeks of
Dasatinib therapy due to risk of hypocalcemia.

12. Patient has the following laboratory values within 28 days before Baseline day 1 of
the Cycle 1:

- Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN)

- Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN

- Serum Na, K+, Mg2+, Phosphate and Calcium > Lower Limit of Normal (LLN)

- Calculated or measured creatinine clearance: ≥ 20 mL/minute

- Hemoglobin, Neutrophil count, Platelets, PT, PTT, Fibrinogen all Grade 0-1

- Corrected serum calcium ≤ 14 mg/dL ( ≤ 3.5 mmol/L).

Exclusion Criteria:

1. Patients with > 2 previous treatment regimens.

2. Multiple myeloma treatment (ie, chemotherapy, biological, immunotherapy or
investigational agent [therapeutic or diagnostic]) administered within 21 days prior
to treatment initiation.

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

4. Pregnant or breast feeding females.

5. 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.

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

7. Concurrent anticoagulation treatment or medications that directly or durably inhibit
platelet function.

8. Malignancy [other than the one treated in this study] which required radiotherapy or
systemic treatment within the past 5 year. Exceptions: basal cell or non metastatic
squamous cell carcinoma of the skin, cervical carcinoma in situ or FIGO Stage 1
carcinoma of the cervix.

9. Concurrent medical condition which may increase the risk of toxicity, including:

- Pleural or pericardial effusion of any grade

10. Clinically significant cardiac disease (NYHA classification III and IV); any of the
following should be considered for exclusion:

1. Uncontrolled angina, congestive heart failure or MI within (6 months)

2. Diagnosed congenital long QT syndrome

3. Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)

4. Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)

5. Subjects with hypokalemia or hypomagnesemia, if it cannot be corrected prior to
dasatinib administration.

11. History of significant bleeding disorder unrelated to cancer, including:

1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
VIII antibodies)

3. Ongoing or recent (< 3 months) significant gastrointestinal bleeding.

12. Concomitant Medications, any of the following should be considered for exclusion:

1. Category I drugs that are generally accepted to have a risk of causing Torsades
de Pointes including: (Patients must discontinue drug 7 days prior to start

- quinidine, procainamide, disopyramide

- amiodarone, sotalol, ibutilide, dofetilide

- erythromycin, clarithromycin

- chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide,

- cisapride, bepridil, droperidol, methadone, arsenic, chloroquine,
domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,

2. The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is
not recommended. The use of antacids should be considered in place of H2
blockers or proton pump inhibitors in patients receiving dasatinib therapy. If
antacid therapy is needed, the antacid dose should be administered at least 2
hours prior to or 2 hours after the dose of dasatinib.

3. Patient may not be receiving any prohibited CYP3A4 inhibitors (see Section 8.6
Prohibited therapies-). Refer to Section Prohibited therapies for other
concomitant medications you may wish to prohibit based on disease/patient

13. Women who:

1. are unwilling or unable to use an acceptable method to avoid pregnancy for the
entire study period and for at least 4 weeks after cessation of study drug, or

2. have a positive pregnancy test at baseline, or

3. are pregnant or breastfeeding. Sexually active women of childbearing potential
(WOCBP) must use an effective method of birth control during the course of the
study, in a manner such that risk of failure is minimized. Prior to study
enrollment, women of childbearing potential must be advised of the importance of
avoiding pregnancy during trial participation and the potential risk factors for
an unintentional pregnancy. All WOCBP MUST have a negative pregnancy test prior
to first receiving dasatinib. If the pregnancy test is positive, the patient
must not receive dasatinib and must not be enrolled in the study.

14. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness.

15. Patient that assume anti-arrhythmic drugs or other medicinal products which led to QT
prolongation and cumulative high dose anthracycline.

16. Patient has active infectious hepatitis type B or C or HIV.

17. Patient has known intolerance to lactose

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:

Partial response rate is a primary study endpoint.

Outcome Description:

Evaluation of tumor status will be conducted at screening and anti-tumor treatment efficacy will be assessed at every cycle according to the International Uniform Criteria for Response in MM. Safety and tolerability are a co-primary endpoint: incidence of grade 3-4 toxicities will support the decision to move to stage 2, together with PR rate once all the patients accrued to the first stage are evaluable.

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Mario Boccadoro, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Divisione Universitaria di Ematologia Ospedale Molinette di Torino


Italy: Ethics Committee

Study ID:




Start Date:

February 2008

Completion Date:

May 2011

Related Keywords:

  • Myeloma
  • relapsed/refractory myeloma patients
  • Progression free survival
  • Overall survival
  • dasatinib
  • Multiple Myeloma
  • Neoplasms, Plasma Cell