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Multiple Myeloma

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Dasatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

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Tyrosine

Dasatinib will be administered continuously at an oral dose of 70 mg BID on Days 1-28 of each 28 day cycle.

In patients with stable disease after 8 weeks on therapy the dasatinib will be increased to 100 mg BID on Days 1-28 on each 28 day cycle.

Ravi Vij, M.D.

To evaluate the response rate (Complete Response \[CR\] and Partial Response \[PR\]) to dasatinib in patients with relapsed, refractory or plateau phase multiple myeloma whose serum paraprotein levels are \>0.5g/dL or urine paraprotein levels are \>1.0g/24 hours.

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.

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

CR requires all of the following:

* Absence of the original monoclonal paraprotein in serum and urine by immunofixation, maintained for a minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal immune response reconstitution does not exclude CR.
* \< 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if biopsy is performed. If absence of monoclonal protein is sustained for 6 weeks it is not necessary to repeat the bone marrow.
* No increase in the size or number of lytic bone lesions (development of a compression fracture does not exclude response).
* Disappearance of soft tissue plasmacytoma

PR requires all of the following:

* 50% reduction in the level of the serum monoclonal paraprotein maintained for a minimum of 6 weeks.

  -Reduction in 24 hr urinary light chain excretion by either \> 90% or to \< 200 mg, maintained for a minimum of 6 weeks.
* 50% reduction in the size of soft tissue plas

Time to response is measured from the start of treatment until the first date that criteria are met for complete response or partial response.

Toxicities were graded using the NCI Common Toxicity Criteria v3.0.

Duration of response is measured from the first date that criteria are met for complete response or partial response until the first date that criteria for relapse or progressive disease are met.

EFS is defined as time from the start of the treatment until the first date that criteria for progressive disease are met, therapy was discontinued for toxicity, or death, whichever occurs first. Those patients alive will be censored at the date of last clinical contact. If progression is based upon serum or urine paraprotein measurements, which must be repeated for confirmation, event-free progression is still measured from the start of treatment until the first date that progression is detected.

Washington University School of Medicine

Dasatinib will be administered continuously at an oral dose of 70 mg BID on Days 1-28 of each 28 day cycle.

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Stage IA

Stage IIA

Stage IIIA

Stage IIIB

Stage I: Hemoglobin (Hb) \> 10g/dL, normal calcium, normal or single plasmacytoma or osteoporosis, Serum paraprotein level \< 5 g/dL if IgG, \< 3 g/dL if IgA, Urinary light chain excretion \< 4 g/24h Stage 2: Not fufilling criteria of Stage I or III Stage III: Hb \< 8.5g/dL, calcium \> 12 mg/dL, 3 or more lytic bone lesions, Serum paraprotein \> 7g/dL if IgG, \> 5 g/dL if IgA, Urinary light chain excretion \> 12g/24h

Stages I, II, and III can be divided into A or B depending on serum creatinine:

A: serum creatinine \< 2 mg/dL (\< 177 μmol/L) B: serum creatinine \> 2 mg/dL (\> 177 μmol/L)

Durie-Salmon Stage

Prior therapies

Immunomodulatory agents

Bortezomib

Anthracycline-containing regimens

Prior autologous stem cell transplant

Beta 2 microglobulin at study entry

Relapsed

Plateau phase

Disease status at study entry

Light chain only

Paraprotein

Normal

Del 13/13q

Complex (including 1 with t4;14)

t9;16

Del 6p

Unavailable

Cytogenetics

Complete response

Partial response

Dasatinib 70 mg BID

In patients with stable disease after 8 weeks on therapy the dasatinib will be increased to 100 mg BID on Days 1-28 on each 28 day cycle.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma	NCT00429949	Relapsed, Refra...	Dasatinib	18 Years -	Washington University School of Medicine
A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma	NCT00429949	Relapsed, Refra...	Dasatinib	18 Years -	Washington University School of Medicine

Spots Global Cancer Trial Database for relapsed, refractory or plateau phase multiple myeloma