Relapsed, Refractory or Plateau Phase Multiple MyelomaPhase 2NCT00429949
A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma
A Phase 2 study testing Dasatinib in people with Relapsed, Refractory or Plateau Phase Multiple Myeloma, run by Washington University School of Medicine at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Relapsed, Refractory or Plateau Phase Multiple Myeloma
- What is being tested?
- Dasatinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2007to Jan 2008
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 20Show fewer
- 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.
Who cannot join
- 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
Show all 41Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington Universtiy in St. Louis
St Louis, Missouri, 63110
About this study
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.
Read the detailed description
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.
- Being tested
- Dasatinib
- Keywords
- Dasatinib, Plateau phase
- Medical subject headings
- Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DasatinibDrug
Also called Sprycel
| Study group | Role | What they receive |
|---|---|---|
| Dasatinib | Experimental | 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. Receives: Drug: Dasatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Completion of treatment (median duration of therapy was 51 days)
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Completion of treatment (median duration of therapy was 51 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Feb 2007 (estimated)
- Study startJan 2007
- Primary completionJan 2008
- Study completionJan 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Relapsed, Refractory or Plateau Phase Multiple MyelomaStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ravi Vij, M.D., Principal investigator, Washington Universtiy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00429949
- Sponsor's protocol ID
- 06-1159
- Status last verified
- Aug 2014
- First submitted
- 31 Jan 2007
- Last updated
- 29 Aug 2014
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 29 Aug 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Dasatinib in the Treatment of Relapsed or Plateau Phase Multiple Myeloma
- ClinicalTrials.gov ID
- NCT00429949
- Acronym / sponsor ID
- 06-1159
- Keywords
- Dasatinib, Plateau phase
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Study start
- Jan 2007
- Primary completion
- Jan 2008 (actual)
- Study completion
- Jan 2008 (actual)
- First posted
- 1 Feb 2007 (estimated)
- Results
- Posted 29 Aug 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dasatinib | Experimental | Drug: DasatinibDasatinib 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Multiple myeloma diagnosed by standard criteria with either relapsed or plateau-phase disease.
- 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:
Key exclusion criteria (41 listed)
- Receiving any of the following therapies or medications:
- 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:
- Cardiac Symptoms or Cardiovascular Disease, including:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DasatinibAlso: Sprycel | Drug | Dasatinib |
Primary outcome
Response Rate [Complete Response (CR) and Partial Response (PR)]
Time frame: Completion of treatment (median duration of therapy was 51 days)
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
5 secondary outcomes
Time to Response
Time frame: Completion of treatment (median duration of therapy was 51 days)
Safety and Tolerability of Dasatinib (Grade III-IV Toxicities)
Time frame: Up to 30 days following end of treatment (median duration of therapy was 51 days)
Duration of Response
Time frame: Completion of treatment (median duration of therapy was 51 days)
Event-free Survival (EFS) for Participants With Plateau Phase Disease
Time frame: Completion of treatment (median duration of therapy was 51 days)
Event-free Survival (EFS) for Participants With Relapsed Disease
Time frame: Completion of treatment (median duration of therapy was 51 days)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Aug 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of MedicineLink provided by the sponsor.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ravi Vij, M.D. principal investigator
Washington Universtiy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Dasatinib in people with Relapsed, Refractory or Plateau Phase Multiple Myeloma, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 41 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Aug 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Response Rate [Complete Response (CR) and Partial Response (PR)] (time frame: Completion of treatment (median duration of therapy was 51 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Aug 2014.