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A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma

Phase 2
18 Years
Not Enrolling
Relapsed, Refractory or Plateau Phase Multiple Myeloma

Thank you

Trial Information

A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma

Studies have confirmed the ability of dasatinib to inhibit numerous kinases (76 of 148
kinases tested in one series).13 Overexpression or dysregulation of a number of kinases have
been implicated in the pathophysiology of MM and could serve as potential targets for
inhibition by dasatinib.

Fibroblast growth factor 3 (FGFR3), which is not normally expressed in plasma cells, is
aberrantly expressed in 15 % of multiple myeloma patients. Its expression results from the
translocation t4;14.14 Dasatinib weakly inhibits FGFR3.13

Another target for inhibition in multiple myeloma is the epidermal growth factor receptor
family, particularly ErbB4. In vitro, ErbB4 was expressed in 4 of 9 myeloma cell lines, and
a panErbB inhibitor induces apoptosis in myeloma cell lines.15 Dasatinib has been shown to
have moderate affinity for ErbB4.13

Members of the src family of protein-tyrosine kinases are also potential targets for therapy
in multiple myeloma. Hematopoietic cell kinase (Hck) is a src family member whose
expression is restricted to hematopoietic cells of the myeloid and B-lymphoid lineages. Hck
mediates IL-6 induced proliferative signals, which are potent growth and survival factors in
multiple myeloma.16 Lyn and Fyn are two additional src family protein-tyrosine kinases that
may serve as targets for therapy in myeloma. Lyn is strongly expressed in myeloma cell
lines, while Fyn expression is variable. Activation of Lyn and Fyn appears requisite to
IL-6-induced proliferation.17 Selective inhibition of Lyn in vitro suppresses IL-6 induced
proliferation.18 Dasatinib has high affinity for both Fyn and Lyn, and inhibition may
reduce IL-6 induced proliferation.13

The receptor tyrosine kinase c-kit is overexpressed in one-third of cases of multiple
myeloma. 19 Inhibition of c-kit with imatinib results in inhibition of proliferation in
vitro.20 Unfortunately, in a phase II clinical study of imatinib in relapsed/refractory
myeloma, there were no responses.21 However, dasatinib binds c-kit with greater avidity than
does imatinib.13

Myeloma cells are heterogeneous in their biological characteristics, such as their
proliferative response to IL-6, as well as their immunophenotypes, including CD45
expression. The promiscuous nature of kinase inhibition by dasatinib may tolerate small
changes in the kinase and remain able to inhibit mutant kinases.

In addition to potential antimyeloma effects of dasatinib, there are potentially additional
benefits. Src plays an essential role in osteoclast function and bone resorption.22 As a Src
inhibitor, dasatinib inhibits bone resorption in vitro. 11 Src inhibition by dasatinib in
patients with multiple myeloma could produce beneficial effects on bone density.

We propose a single-arm, phase II, open-label study of dasatinib in patients with relapsed
or plateau-phase multiple myeloma.

Inclusion Criteria

Inclusion Criteria

- Multiple myeloma diagnosed by standard criteria with either relapsed or plateau-phase

- Relapsed: At least 1 prior therapy for multiple myeloma with documented evidence
of progression on the most recent treatment.

- Plateau-phase: subjects with myeloma who had a response to their most recent
multiple myeloma therapy (including autologous transplantation or other
investigational agents) and have residual detectable monoclonal protein in their
serum or urine that has been stable for greater than or equal to 3 months (+/-
25% change in M-protein).

- Measurable levels of monoclonal protein in serum (greater than or equal to 0.5 g/dL)
or urine (greater than or equal to 1.0 g/24 hr).

- Age 18 years or older.

- ECOG performance status of less than or equal to 2.

- Acceptable organ and marrow function as defined below:

- Hemoglobin of greater than or equal to 8 gm/dL

- Absolute neutrophil count of greater than or equal to 500/mm3

- Platelets of greater than or equal to 50,000/mm3

- PT and PTT of less than or equal to 1.5 times the institutional Upper Limit of
Normal (ULN)

- Total bilirubin of less than or equal to 2.0 times the institutional ULN
institutional ULN

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

- Serum Na, K+, Mg2+, Phosphate and Ca2+ greater than or equal to Lower Limit of
Normal (LLN)

- Serum Creatinine of less than or equal to 1.5 times the institutional ULN

- Ability to understand and the willingness to sign a written informed consent

- Ability to take oral medication (dasatinib must be swallowed whole)

- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (sensitivity of less than or equal to 25IU HCG/L) within 72 hours prior to the
start of study drug administration

- Persons of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 4 weeks after study drug is

- Signed written informed consent including HIPAA according to institutional

Exclusion Criteria

- Receiving any of the following therapies or medications:

- Any investigational agents within 30 days.

- Drugs that are generally accepted to have a risk of causing Torsade de Pointes

- 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, lidoflazine

- Subjects who have discontinued any of these medications must have a wash-out
period of at least 7 days prior to the first dose of dasatinib.

- Medications known to be potent CYP3A4 inhibitors (See Appendix D).

- 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 (See
section for important cautions regarding use of antacids.)

- Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy.

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

- Prior therapy with dasatinib

- Biopsy proven amyloidosis.

- History of other malignancy (except for basal cell or squamous cell carcinoma of the
skin or carcinoma in situ of the cervix or breast) which required radiotherapy or
systemic treatment within the past 5 years.

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

- Pleural or pericardial effusion of any grade

- Clinically-significant coagulation or platelet function disorder (e.g. known von
Willebrand's disease)

- Cardiac Symptoms or Cardiovascular Disease, including:

- Myocardial infarction within 6 months

- Uncontrolled angina within 6 months

- Congestive heart failure within 6 months

- Diagnosed or suspected congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes). Any
subject with a history of any arrhythmia should be discussed with the
Investigator prior to entry into the study.

- Prolonged QTc interval on pre-entry electrocardiogram (greater than 450 msec) on
Bazett's correction. However, if Bazett's correction is high (i.e., greater than
450 msec) and Fridericia is less than or equal to 450 msec, the subject is

- Subjects with hypokalemia or hypomagnesemia if it cannot be corrected

- Dementia or altered mental status that would prohibit the understanding or rendering
of informed consent

- History of significant bleeding disorder unrelated to cancer, including:

- Diagnosed congenital bleeding disorder (e.g., von Willebrand's disease)

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

- Ongoing or recent (less than or equal to 3 months) significant gastrointestinal

- Women:

- 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

- have a positive pregnancy test at baseline, or

- are breastfeeding.

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

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

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.

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:

Evaluate the response rate (complete response and partial response) whose serum paraprotein levels are >= 0.5g/dL or urine paraprotein levels are >=1.0g/24 hours

Outcome Time Frame:

Completion of treatment

Safety Issue:


Principal Investigator

Ravi Vij, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Washington Universtiy


United States: Food and Drug Administration

Study ID:




Start Date:

January 2007

Completion Date:

January 2008

Related Keywords:

  • Relapsed, Refractory or Plateau Phase Multiple Myeloma
  • Dasatinib
  • Plateau phase
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



Washington Universtiy in St. Louis St. Louis, Missouri  63110