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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Relapsed, Refractory or Plateau Phase Multiple Myeloma

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Multiple myeloma diagnosed by standard criteria with either relapsed or plateau-phase disease. 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 document. 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 stopped. Signed written informed consent including HIPAA according to institutional guidelines. 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 including: 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 5.5.2.3 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 eligible. 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 bleeding 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib<br>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. | Drug: Dasatinib<br> <br> * Other names: Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate [Complete Response (CR) and Partial Response (PR)] | 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 | Completion of treatment (median duration of therapy was 51 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Response | Time to response is measured from the start of treatment until the first date that criteria are met for complete response or partial response. | Completion of treatment (median duration of therapy was 51 days) | 
| Safety and Tolerability of Dasatinib (Grade III-IV Toxicities) | Toxicities were graded using the NCI Common Toxicity Criteria v3.0. | Up to 30 days following end of treatment (median duration of therapy was 51 days) | 
| Duration of Response | 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. | Completion of treatment (median duration of therapy was 51 days) | 
| Event-free Survival (EFS) for Participants With Plateau Phase Disease | 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. | Completion of treatment (median duration of therapy was 51 days) | 
| Event-free Survival (EFS) for Participants With Relapsed Disease | 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. | Completion of treatment (median duration of therapy was 51 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dasatinib, Plateau phase