Dasatinib in Combination With Revlimid (and Dexamethasone)

Study Overview
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Brief Summary
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The purpose of this study was to determine the safety and tolerability of dasatinib when given in combination with lenalidomide and a low dose dexamethasone for the treatment of relapsed or refractory multiple myeloma.

Official Title
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A Phase I Single Arm Dose Escalation Study of the Combination of Dasatinib (Sprycel®) With Lenalidomide (Revlimid®) and Dexamethasone in Subjects With Relapsed and/ or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Dasatinib, 70 mg + Lenalidomide, 15 mg + Dexamethasone, 40 mg
* Drug: Dasatinib, 70 mg + Lenalidomide, 20 mg + Dexamethasone, 40 mg
* Drug: Dasatinib, 100 mg + Lenalidomide, 20 mg + Dexamethasone, 40 mg
* Drug: Dasatinib, 100 mg + Lenalidomide, 25 mg + Dexamethasone, 40 mg
* Drug: Dasatinib, 140 mg + Lenalidomide, 25 mg + Dexamethasone, 40 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide written informed consent Men and women age ≥ 18 years Confirmed diagnosis of multiple myeloma (MM) with measurable disease assessed within 1 month prior to treatment initiation Evidence of relapsed or refractory disease and at least one prior therapy for MM Eastern Cooperative Oncology Group Scale (ECOG) Performance Status of 0 - 2 Last MM treatment at least 21 days prior to treatment initiation• Bone marrow transplant (BMT) at least 3 months prior to treatment initiation Required baseline hematology and chemistry parameters Resolution of acute toxicity due to prior therapy to Grade <2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Exclusion Criteria: Women who are pregnant or breastfeeding Men whose sexual partners are women of child bearing potential (WOCBP) or WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least one month (4 weeks) before and for at least one month (4 weeks) after the last dose of study medication. Clinically significant cardiac disease (New York Heart Association [NYHA] Class III or IV) Abnormal corrected QT interval using Fridericia's formula (QTcF) interval prolonged (> 450 msec) Medications that are generally considered to have a risk of causing Torsades de Pointes Malabsorption syndrome or uncontrolled gastrointestinal toxicities Clinically significant pleural effusion in the previous 12 months or current ascites Clinically-significant coagulation or platelet function disorder Dementia, chronic medical or psychiatric condition, or laboratory abnormality Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality, serious uncontrolled medical disorder or active infection Intolerance to dasatinib and/or lenalidomide Subjects with a history of severe rash, hypersensitivity reaction or anaphylaxis related to prior thalidomide treatment

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, 70 mg + Lenalidomide, 15 mg + Dexamethasone, 40 mg<br>Participants received a combination of dasatinib, 70 mg QD, lenalidomide, 15 mg QD, and dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22, in 28-day cycles. | Drug: Dasatinib, 70 mg + Lenalidomide, 15 mg + Dexamethasone, 40 mg<br>* Participants received dasatinib, 70 mg once daily (QD), for 28 days plus lenalidomide, 15 mg QD, for 21 days plus dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22.<br>* Other names: Revlimid®;|
| Experimental: Dasatinib, 70 mg + Lenalidomide, 20 mg + Dexamethasone, 40 mg<br>Participants received a combination of dasatinib, 70 mg QD, lenalidomide, 20 mg QD, and dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22, in 28-day cycles. | Drug: Dasatinib, 70 mg + Lenalidomide, 20 mg + Dexamethasone, 40 mg<br>* Participants received dasatinib, 70 mg QD, for 28 days plus lenalidomide, 20 mg QD, for 21 days, plus dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22.<br>* Other names: Revlimid®;|
| Experimental: Dasatinib, 100 mg + Lenalidomide, 20 mg + Dexamethasone, 40 mg<br>Participants received a combination of dasatinib, 100 mg QD, lenalidomide, 20 mg QD, and dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22, in 28-day cycles. | Drug: Dasatinib, 100 mg + Lenalidomide, 20 mg + Dexamethasone, 40 mg<br>* Participants received dasatinib, 100 mg QD, for 28 days, plus lenalidomide, 20 mg QD, for 21 days, plus dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22.<br>* Other names: Revlimid®;|
| Experimental: Dasatinib, 100 mg + Lenalidomide, 25 mg + Dexamethasone, 40 mg<br>Participants received a combination of dasatinib, 100 mg QD, lenalidomide, 25 mg QD, and dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22, in 28-day cycles. | Drug: Dasatinib, 100 mg + Lenalidomide, 25 mg + Dexamethasone, 40 mg<br>* Participants received dasatinib, 100 mg QD, for 28 days, plus lenalidomide, 25 mg QD, for 21 days, plus dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22.<br>* Other names: Revlimid®;|
| Experimental: Dasatinib, 140 mg + Lenalidomide, 25 mg + Dexamethasone, 40 mg<br>Participants received a combination of dasatinib, lenalidomide, and dexamethasone in varying doses in 28-day cycles. | Drug: Dasatinib, 140 mg + Lenalidomide, 25 mg + Dexamethasone, 40 mg<br>* Participants received dasatinib, 140 mg QD, for 28 days, plus lenalidomide, 25 mg QD, for 21 days, plus dexamethasone, 40 mg QD, weekly on Days 1, 8, 15, and 22. Cohort includes 4 participants who received treatment during the dose-finding phase and 13 participants who received treatment in the dose-expansion phase.<br>* Other names: Revlimid®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose (RP2D) of the Combination (Dasatinib + Lenalidomide + Dexamethasone) | The RP2D was based on the MTD which was defined as the maximum combined dose producing dose limiting toxicity (DLT) in < 33% of participants treated at the individual dose levels in the combination. The MTD is considered the last dose level combination tested just below the maximum administered dose (MAD) level combination and for which DLTs were observed in less than or equal to 33% of participants during the escalation and expansion phase. If MTD was not reached Please refer to Outcome Measure 2 for the complete definition of DLT. | From the date of first dose to end of treatment (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). | 
| Number of Participants With Dose-limiting Toxicity (DLT) | DLTs: At least possibly drug-related AEs occurring during the first cycle of treatment and are:GR4 neutropenia >5 days/neutropenic fever;platelet count <10000mm^3 on >1 occasion;GR4 fatigue,or 2-point decline in ECOG performance status;>=GR3 nausea,diarrhea,and vomiting despite medical intervention;Any other clinically significant non-hematologic toxicity of >=GR3 considered not related to underlying MM;Any GR3/4 laboratory abnormality requiring hospitalization;dose interruption of either dasatinib and/or lenalidomide for >15 days due to any toxicity related to treatment with the combination. | From the date of first dose until at least 30 days after the last dose of study drug (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). | 
| Number of Participants in the Dose Escalation Phase Who Reached Maximum Tolerated Dose (MTD) of Dasatinib With Lenalidomide and Dexamethasone | The MTD is considered the last dose level combination tested just below the maximum administered dose (MAD) level combination and for which DLTs were observed in less than 33% of participants during the escalation and expansion phase. Please refer to outcome 2 for the complete definition of DLT. If the MTD was not reached at the highest dose administered as defined by protocol, the highest dose (dasatinib 140 mg QD + lenalidomide 25 mg QD) administered was selected for the dose expansion phase of the study. | From the date of first dose to end of treatment (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). | 
| Number of Participants Who Died, Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation | AE: New untoward medical occurrence or worsening of a preexisting medical condition that does not have causal relationship with this treatment. SAE: Untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency/abuse; life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization/prolongs existing hospitalization. Grade 1= Mild; Grade 2= Moderate; Grade 3= Severe; Grade 4 = Life-threatening or disabling. | Baseline (pretreatment), from the date of first dose until at least 30 days after the last dose of study drug (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). | 
| Number of Participants With Hematology Abnormalities (Worst On-study Grade vs Baseline): Leukopenia, Neutropenia, Thrombocytopenia, and Anemia | As per NCI CTCAE Version 3.0 criteria. Grade (GR)1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. White blood cell (WBC):GR1=<LLN(lower limit of normal)-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3:<2.0-1.0*10^9/L; GR4:<1.0*10^9/L. LLN=lower limit of normal. Absolute Neutrophil Count (ANC): GR1=<LLN-1.5*10^9/L; GR2=<1.5-1.0*10^9/L; GR3:<1.0-0.5*10^9/L; GR4:<0.5*10^9/L. Hemoglobin: GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3:<8.0-6.5g/dL; GR4:<6.5g/dL. Platelets: GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3:<50.0-25.0*10^9/L; GR4:<25.0*10^9/L. BL=Baseline; PBL=post baseline. | Baseline (pretreatment); Cycles 1 and 2 (within 24 hours of Days 1, 4, 8, 11, 15, 18, 21, and 25); beyond Cycle 2 (within 24 hours of Days 1 and 15,off treatment visit ) (median duration of dasatinib treatment=5.2 mo [range 0 to 33 mo]) | 
| Number of Participants With Serum Chemistry Abnormalities (Worst On-study Grade vs Baseline): Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Total Bilirubin (TB), and Serum Creatinine (SC) | Grading as per NCI CTCAE Version 3.0 criteria. GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Aspartate aminotransferase (AST) and alanine aminotransferase(ALT): GR1=>ULN-2.5*ULN (upper limit of normal); GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4:>20.0*ULN; TB:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN; SC: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN. BL=Baseline; PBL=post baseline. | Baseline (pretreatment); Cycles 1 and 2 (within 24 hours of Days 1, 4, 8, 11, 15, 18, 21, and 25); beyond Cycle 2 (within 24 hours of Days 1 and 15,off treatment visit ) (median duration of dasatinib treatment=5.2 mo [range 0 to 33 mo]) | 
| Number of Participants With Serum Chemistry Abnormalities (Worst On-study Grade vs Baseline): High Calcium, Low Calcium, Low Magnesium, and Low Phosphorus | Grading as per NCI CTCAE Version 3.0 criteria. GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Calcium (low): GR1: <LLN - 8.0 mg/dL, GR2: <8.0 - 7.0 mg/dL, GR3: <7.0 - 6.0 mg/dL, GR4: <6.0 mg/dL. Calcium (High): GR1: >ULN - 11.5 mg/dL, GR2: >11.5 - 12.5 mg/dL, GR3: >12.5 - 13.5 mg/dL, GR4: >13.5 mg/dL. Magnesium (Low): GR1: <LLN - 1.2 mg/dL, GR2: <1.2 - 0.9 mg/dL, GR3: <0.9 - 0.7 mg/dL, GR4: <0.7 mg/dL. Phosphorus (low): GR1: <LLN - 2.5 mg/dL, GR2: <2.5 - 2.0 mg/dL, GR3: <2.0 - 1.0 mg/dL, GR4: <1.0 mg/dL. BL=Baseline; PBL=post baseline. | Baseline (pretreatment); Cycles 1 and 2 (within 24 hours of Days 1, 4, 8, 11, 15, 18, 21, and 25); beyond Cycle 2 (within 24 hours of Days 1 and 15,off treatment visit ) (median duration of dasatinib treatment=5.2 mo [range 0 to 33 mo]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response and Very Good Partial Response | Response criteria were based on The International Uniform Response Criteria for Multiple Myeloma (with a slight modification). Complete response was achieved when there was negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. Very good partial response was achieved when serum and urine M-component was detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component < 100 mg per 24 hour. | Baseline, At the end of the treatment period (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). | 
| Number of Participants With Partial Response | Partial response was achieved when there was ≥50% reduction of serum M-protein (Mpr)and reduction in 24 hour urinary Mpr by ≥90% or to <200 mg/24 hr. If the serum and urine Mpr were unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC) levels was required in place of the Mpr criteria. If serum, urine Mpr, and serum FLC assay were unmeasurable, ≥50% reduction in plasma cells was required in place of Mpr, provided baseline bone marrow plasma cell percentage was ≥30%; a ≥50% reduction in the size of soft tissue plasmacytomas was also required. | Baseline, at the end of the treatment period (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). | 
| Number of Participants With Minimal Response | Response criteria was based on The International Uniform Response Criteria for Multiple Myeloma (with a slight modification). Minimal Response was achieved when there was 25% to 49% reduction of serum M-Protein, 50% to 89% reduction in 24 hour urinary M-protein which still exceeded 200 mg/24 hour. If the serum and urine M-protein were unmeasurable, 25% to 49% reduction in plasma cells was required. In addition, if present at baseline, a 25% to 49% reduction in the size of soft tissue plasmacytomas was also required. | Baseline, at the end of the treatment period (median duration of dasatinib treatment=5.2 months [range 0 to 33 months]). |