Japanese Phase 2 Study to Evaluate the Efficacy and Safety of Pomalidomide in Subjects With Relapsed and Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of pomalidomide in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma.

Official Title
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A Phase 2, Multicenter, Single-arm, Open-label Study in Japan to Evaluate the Efficacy and Safety of Pomalidomide (CC-4047) in Combination With Dexamethasone in Subjects With Relapsed and Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Must be ≥ 20 years of age at the time of signing the informed consent document. 2. The subject must understand and voluntarily sign an informed consent document before any study related assessments/procedures are conducted. 3. Must be able to adhere to the study visit schedule and other protocol requirements. 4. Have a documented diagnosis of multiple myeloma and have relapsed and refractory disease. Subjects must have received at least 2 prior therapies. Subjects must have relapsed after having achieved at least stable disease for at least one cycle of treatment to at least one prior regimen and then developed progressive disease(PD). Subjects must also have documented evidence of progressive disease(PD) during or within 60 days (measured from the end of the last cycle) of completing treatment with the last antimyeloma drug regimen used just prior to study entry (refractory disease). 5. Subjects must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of bortezomib (either in separate regimens or within the same regimen). 6. Subjects must have documented diagnosis of multiple myeloma and have measurable disease (serum M-protein ≥ 0.5 g/dL or urine M-protein ≥ 200 mg/24 hours). 7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. 8.Must agree to comply to pomalidomide Pregnancy Prevention Risk Management Plan. Exclusion Criteria: 1. Pregnant or breastfeeding females 2. Hypersensitivity to thalidomide, lenalidomide, or dexamethasone 3. ≥ Grade 3 rash during prior thalidomide or lenalidomide therapy 4. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment will not be eligible to participate in this study 5. Any of the following laboratory abnormalities: Absolute neutrophil count < 1,000/µL Platelet count < 75,000/µL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 30,000/µL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells Creatinine Clearance < 45 mL/min according to Cockcroft-Gault formula Cockcroft-Gault estimation of Creatinine Clearance: Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L) Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior Red blood cell transfusion or recombinant human erythropoietin use is permitted) Serum glutamic oxaloacetic transaminase(SGOT)/aspartate aminitransferase(AST) or serum glutamic pyruvic transaminase(SGPT)/alanine aminotransferase(ALT) > 3.0 x upper limit of normal(ULN) Serum total bilirubin > 2.0 mg/dL (34.2 μmol/L); or ≥ 3.0 x upper limit of normal (ULN) for subjects with hereditary benign hyperbilirubinemia. 6. Subjects with any one of the following: Congestive heart failure (New York Heart Association Class III or IV) Myocardial infarction within 12 months prior to starting study treatment Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris 7. Peripheral neuropathy ≥ Grade 2. 8. Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following: Basal or Squamous cell carcinoma of the skin Carcinoma in situ of the cervix or breast Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b) 9. Known infection with human immunodeficiency virus (HIV) antibody positive, hepatitis B virus surface antigen (HBsAg) positive or hepatitis C virus antibody (HCVAb) positive. If negative for hepatitis B virus surface antigen (HBsAg) but hepatitis B core antibody (HBcAb) and/or hepatitis B surface antibody (HBsAb) positive status, a hepatitis B virus DNA test will be performed and if positive the subject will be excluded. 10. Incidence of gastrointestinal disease that may significantly alter the absorption of pomalidomide. 11. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 12. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 13. Any condition that confounds the ability to interpret data from the study. 14. Previous therapy with pomalidomide. 15. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of treatment. 16. Subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis, and lupus, which likely need additional steroid or immunosuppressive treatments in addition to the study treatment. Includes subjects receiving corticosteroids (> 10 mg/day of prednisone or equivalent) within 3 weeks prior to enrollment. 17. Subjects who received any of the following within the last 14 days of initiation of study treatment: Plasmapheresis Major surgery (kyphoplasty is not considered major surgery) Radiation therapy Use of any antimyeloma drug therapy. 18. Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study treatment and who have not discontinued immunosuppressive treatment for at least 4 weeks prior to initiation of study treatment and are currently dependent on such treatment. 19. Subjects who are planning for or who are eligible for stem cell transplant.

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pomalidomide plus dexamethasone<br> | Drug: Pomalidomide<br>* 4 mg oral pomalidomide once daily Days 1-21 of each 28-day cycle<br>* Other names: CC-4047;Drug: Dexamethasone<br>* 40 mg or 20 mg oral dexamethasone once daily on Days 1, 8, 15, 22 of each 28-day cycle<br>* Other names: LenaDex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myeloma Response Rate Based on the International Myeloma Working Group (IMWG) Uniform Response Criteria | Myeloma response was defined as a best overall response of stringent complete response (SCR), complete response (CR), very good partial response (VGPR) or partial response (PR) SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to < 200 mg/24 hours. In addition to the above, if present at baseline a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required. | From the first dose until the data cut-off date of 03 Sept 2014; Maximum time in follow-up was 36.0 weeks. | 
| Myeloma Response Rate Based on the International Myeloma Working Group (IMWG) Uniform Response Criteria (Later Cut-off Date) | Myeloma response was defined as a best overall response of stringent complete response (SCR), complete response (CR), very good partial response (VGPR) or partial response (PR) SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to < 200 mg/24 hours. In addition to the above, if present at baseline a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required. | From the first dose until the final data cut-off date of 25 September 2015; maximum duration on treatment was 80.9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myeloma Response Rate Based on European Group for Blood and Marrow Transplantation (EBMT) Criteria | Myeloma response was defined as a best overall response of complete response (CR) or partial response (PR) CR is defined as: - Absence of original monoclonal paraprotein in serum and urine by immunofixation maintained at least 42 days. - <5% plasma cell in bone marrow aspirate and on bone marrow biopsy, if performed. - No increase in size or number of lytic bone lesions. - Disappearance of soft tissue plasmacytomas. PR requires all of the following: - ≥ 50% reduction in level of serum monoclonal paraprotein, maintained at least 42 days. - Reduction in 24-hour urinary light chain extraction by ≥ 90% or to < 200 mg, maintained at least 42 days. - For patients with non-secretory myeloma, ≥ 50% reduction in plasma cells in bone marrow aspirate and on biopsy, if performed, for at least 42 days. - ≥ 50% reduction in the size of soft tissue plasmacytomas. - No increase in size or number of lytic bone lesions. | From first dose until the data cut-off date of 03 September 2014; maximum time in follow-up was 36.0 weeks | 
| Time to Response | Time to response was calculated as the time from the first dose to the initial documented response (partial response or better) based on IMWG criteria. SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to < 200 mg/24 hours. If present at baseline a ≥ 50% reduction in size of soft tissue plasmacytomas is also required. | From the first dose until the data cut-off date of 03 September 2014. Maximum time on follow-up was 36.0 weeks. | 
| Myeloma Response Rate Based on European Group for Blood and Marrow Transplantation (EBMT) Criteria (Later Cut-off Date) | Myeloma response was defined as a best overall response of complete response (CR) or partial response (PR) CR is defined as: - Absence of original monoclonal paraprotein in serum and urine by immunofixation maintained at least 42 days. - <5% plasma cell in bone marrow aspirate and on bone marrow biopsy, if performed. - No increase in size or number of lytic bone lesions. - Disappearance of soft tissue plasmacytomas. PR requires all of the following: - ≥ 50% reduction in level of serum monoclonal paraprotein, maintained at least 42 days. - Reduction in 24-hour urinary light chain extraction by ≥ 90% or to < 200 mg, maintained at least 42 days. - For patients with non-secretory myeloma, ≥ 50% reduction in plasma cells in bone marrow aspirate and on biopsy, if performed, for at least 42 days. - ≥ 50% reduction in the size of soft tissue plasmacytomas. - No increase in size or number of lytic bone lesions. | From the first dose until the final data cut-off date of 25 September 2015; maximum duration on treatment was 80.9 weeks | 
| Time to Response (Later Cut-off Date) | Time to response was calculated as the time from the first dose to the initial documented response (partial response or better) based on IMWG criteria. SCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to < 200 mg/24 hours. If present at baseline a ≥ 50% reduction in size of soft tissue plasmacytomas is also required. | From the first dose until the final data cut-off date of 25 September 2015; maximum duration on treatment was 80.9 weeks | 
| Kaplan-Meier Estimates of Duration of Response | Duration of response (calculated for responders only) was defined as time from the initial documented response (partial response or better) to confirmed disease progression, based on IMWG criteria. | From first dose until the data cut-off date of 03 September 2014; maximum time for follow-up was 36 weeks | 
| Kaplan-Meier Estimates of Duration of Response (Later Cut-off Date) | Duration of response (calculated for responders only) was defined as time from the initial documented response (partial response or better) to confirmed disease progression, based on IMWG criteria. | From the first dose until the final data cut-off date of 25 September 2015; maximum duration on treatment was 80.9 weeks | 
| Kaplan-Meier Estimates of Progression-free Survival (PFS) | PFS was calculated as the time from the first dosing to the first documented progressive disease, as determined by the investigators based on the IMWG Uniform Response criteria, or death, whichever occurred earlier | From the first dose until the data cut-off date of 03 September 2014; maximum time on treatment was 36.0 weeks | 
| Kaplan-Meier Estimates of PFS (Later Cut-off Date) | PFS was calculated as the time from the first dosing to the first documented progressive disease, as determined by the investigators based on the IMWG Uniform Response criteria, or death, whichever occurred earlier | From the first dose until the final data cut-off date of 25 September 2015; maximum duration on treatment was 80.9 weeks | 
| Number of Participants With Adverse Events | Relation to study drug was assessed by the Investigator as either suspected or not suspected. Counts represent the suspected relationship. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0): 1= Mild 2= Moderate 3= Severe 4= Life-threatening and 5= Death related to AE. Serious AEs (SAEs) were those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. Treatment Emergent Adverse Event (TEAE) was defined as any AE occurring on or after the first treatment of the study medication and within 28 days after the last dose. | From first dose of study drug to final data cut-off date of 25 Sept 2015, maximum duration on treatment was 80.9 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pomalidomide,, CC-4047,, Dexamethasone,, Relapsed and refractory multiple myeloma,, phase 2