Safety Study of Dasatinib With Bortezomib (Velcade®) and Dexamethasone for Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the safety and tolerability of dasatinib with bortezomib in the treatment of relapsed or refractory multiple myeloma.

Official Title
-----------------
A Phase I Study of Dasatinib With Bortezomib (Velcade®) and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Dasatinib
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Confirmed diagnosis of multiple myeloma with measurable disease Evidence of relapsed or refractory disease and at least 2 prior therapies for multiple myeloma Eastern Cooperative Oncology Group Performance Status of 0 - 2 Last treatment for multiple myeloma not within 21 days prior to study treatment initiation Bone marrow transplant not within 3 months prior to study treatment initiation Required baseline hematology and chemistry parameters. Key Exclusion Criteria: Clinically significant cardiac disease (New York Heart Association Class III or IV) Abnormal QT interval corrected for heart rate using Fridericia's formula prolonged (>450 msec) after electrolytes have been corrected on baseline electrocardiogram Malabsorption syndrome or uncontrolled gastrointestinal toxicities Dementia, chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation Clinically significant pleural effusion in the previous 12 months or current ascites Clinically significant coagulation or platelet function disorder Intolerance to dasatinib and/or bortezomib Acute diffuse infiltrative pulmonary disease Prior or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer currently in complete remission, cervical carcinoma in situ, or any other cancer from which the participant has been disease-free for 3 years.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib + Bortezomib + Dexamethasone<br>Phase I dose escalation study | Drug: Dasatinib<br>* Tablets; oral; approximately 2 years on study, depending on response; 50 mg once daily (QD), 100 mg QD, 140 mg QD<br>* Other names: BMS-354825;Drug: Bortezomib<br>* Powder; intravenous; approximately 2 years on study, depending on response; 1.0 mg/m^2 QD, 1.3 mg/m^2 QD<br>* Other names: Velcade®;Drug: Dexamethasone<br>* Tablets; oral; approximately 2 years on study, depending on response; 20 mg QD<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended MTD of Dasatinib in Combination With Bortezomib and Dexamethasone | MTD is defined as the dose level combination below the dose level that produces a dose-limiting toxicity in at least 2 out of 6 or fewer participants in that cohort. If MTD is not reached, the recommended MTD is the maximum dose that the participants received. | Days 1 to 21 | 
| MTD and Recommended MTD of Bortezomib in Combination With Dasatinib and Dexamethasone | MTD is defined as the dose level combination below the dose level that produces a dose-limiting toxicity in at least 2 out of 6 or fewer participants in that cohort. If MTD is not reached, the recommended dose is the maximum dose that the participants received. | Days 1 to 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Tumor Response Rate (RR) As Assessed Using International Uniform Response Criteria for Multiple Myeloma and Criteria of the European Bone Marrow Transplant Registry | S=serum; U=urine; MP=M-protein; ST=soft tissue, PC=plasmacytomas; IF=immunofixation; BL=baseline. RR calculated on best response any time. CR=MP undetectable by IF, ≤5% plasma cells in bone marrow, and no ST PC. VGPR=MP detectable by IF, or ≥90% drop in S MP and U MP<100 mg/24h. PR= ≥50% drop in S MP and ≥90% drop in U MP or U protein <200 mg/24h, ≥50% drop in BL ST PC size. MR= ≥25% to <50% drop in S MP and ≥50% to <90% drop in U MP and ≥25% to <50% drop in BL ST PC. SD=Not CR, VGPR, PR, or MR. PD= ≥25% rise in S or U M-component; new/increased size of bone lesions, ST PC, or hypercalcemia. | Day 1 until last tumor assessment (maximum reached: 9 months) | 
| Duration of Response | Duration of response calculated for those with best response=CR (M-protein [MP] undetectable by immunofixation [IF], ≤5% plasma cells in bone marrow, no soft tissue plasmacytomas); VGPR (MP detectable by IF, or ≥90% drop in serum [S] MP and urine [U] MP<100 mg/24h); PR(≥50% drop in S MP and ≥90% drop in U MP or U protein <200 mg/24h, ≥50% drop in BL ST PC size); or MR (≥25% to <50% drop in S MP and ≥50% to <90% drop in U MP and ≥25% to <50% drop in BL ST PC). Duration of response calculated from day criteria for CR, VGPR, PR, and MR were met until progression or death, whichever came first. | First occurrence of response to disease progression or death, whichever occurred first (maximum reached: 12.2 months) | 
| Progression-free Survival | Progression-free survival was defined as the time from start of treatment until progression or death, whichever occurred first. Participants were to be followed-up for 12 months following the last dose of dasatinib for progression and survival. PFS was analyzed for the all-treated population. | Day 1 to disease progression or death, whichever came first (maximum reached: 14 months) | 
| Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Adverse Events (AEs) Leading to Discontinuation, AEs Leading to Discontinuation, AEs, and Drug-related AEs by Grade | An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=possibly, probably, or certainly related to or of unknown relationship to study treatment. Grade 3=severe; Grade 4=life-threatening. | Continuously from Day 1 until last day of study medication + 30 days (maximum reached: 10 months) |