Study of Tabalumab (LY2127399) in Japanese Participants With Relapsed or Refactory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and effect on the body of Tabalumab (LY2127399) in combination with bortezomib and dexamethasone in Japanese participants with relapsed or refractory multiple myeloma (MM).

Detailed Description
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The study has 3 cohorts. Cohort 2 and cohort 2-SC will be conducted in parallel with some data presented combined. Cohort 1 - Participants will receive 100 mg Tabalumab (LY2127399) intravenously (IV), 1.3 milligram per square meter (mg/m^2) bortezomib IV, and 20 mg dexamethasone orally. Cohort 2 - Participants will receive 300 mg Tabalumab (LY2127399) IV, 1.3 mg/m^2 bortezomib IV, and 20 mg dexamethasone orally. Cohort 2-SC - Participants will receive 300 mg Tabalumab (LY2127399) IV, 1.3 mg/m^2 bortezomib subcutaneously (SC), and 20 mg dexamethasone orally. Cohort 2-SC was added per protocol amendment in February 2013.

Official Title
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A Phase 1 Study of Tabalumab (LY2127399) in Combination With Bortezomib and Dexamethasone in Japanese Patients With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: Tabalumab
* Drug: Bortezomib IV
* Drug: Bortezomib SC
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have relapsed or refractory MM treated with at least 1 prior regimen. Prior therapy with bortezomib is allowed if there was previously at least a minimal response (MR). Have measurable disease as defined by one or more of the following: serum M-protein concentration ≥ 1 g/dL (10 g/L) urine monoclonal light chain concentration ≥ 200 mg/24 hours as determined by urine protein electrophoresis involved serum free light chain (SFLC) concentration ≥ 10 mg/dL (100 mg/L) and an abnormal SFLC ratio Have adequate organ function including: Absolute neutrophil count (ANC) ≥ 1000/microliter Platelet (PLT) count ≥ 75,000/microliter Hemoglobin (Hgb) ≥ 8.0 g/dL Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (if total is elevated check direct and, if normal, participant is eligible) Aspartate transaminase (AST) and alanine aminotransferase (ALT) are ≤ 3 x ULN Serum creatinine ≤ 3.0 mg/dL. Have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≤ 2. Have discontinued all previous therapies for cancer, including chemotherapy, surgery, and radiotherapy for at least 2 weeks (6 weeks for mitomycin-C or nitrosoureas) before study enrollment and recovered from the acute effects of therapy. Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for 4 months following the last dose of study drug. Females with childbearing potential: Must have had a negative urine or serum pregnancy test <7 days before the first dose of study drug. Have an estimated life expectancy of ≥16 weeks, in the opinion of the investigator. Exclusion Criteria: Have received treatment within 30 days of the initial dose of study drug with an experimental agent for non-cancer indications that has not received regulatory approval for any indication. Have one or more serious preexisting medical conditions that, in the opinion of the investigator, would preclude participation in this study. Have an uncontrolled infection. Females who are pregnant or breastfeeding. Have known positive test results for human immunodeficiency virus (HIV), hepatitis B*, or hepatitis C antibodies (HCAb). * Have evidence of or test positive for hepatitis B. A positive test for hepatitis B is defined as: positive for hepatitis B surface antigen (HBsAg+). OR positive for anti-hepatitis B core antibody and positive for hepatitis B deoxyribonucleic acid (HBV DNA). OR positive for anti-hepatitis B surface antibody (HBsAb+) and positive for hepatitis B deoxyribonucleic acid (HBV DNA). Have ≥ Grade 2 peripheral neuropathy or any grade with pain as assessed using the Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v 4.03). Have previously received an allogenic hematopoietic stem cell transplant. Have previously received treatment with an experimental agent that targets B-cell activating factor (BAFF). Have a corrected QT (QTc) interval >470 msec on their baseline electrocardiogram (ECG). Have interstitial pneumonitis (interstitial pneumonia) or pulmonary fibrosis manifested as opacity on chest X-ray or computed tomography (CT) scan. Have had another active malignancy within the past 5 years.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg Tabalumab+Bortezomib (BTZ)IV+Dexamethasone (Dex)<br>Cohort 1. 100 mg tabalumab (LY2127399) intravenously (IV) on day 1 of each cycle, each cyle is 21 days. Bortezomib (BTZ), 1.3 milligram per square meter (mg/m^2), IV on days 1, 4, 8, 11 of Cycle 1-8, then on days 1, 8, 15, 22 from Cycle 9 onward. Oral dexamethasone (Dex), 20 mg/day, on day of and day after BTZ. | Biological: Tabalumab<br>* Administered IV<br>* Other names: LY2127399;Drug: Bortezomib IV<br>* Administered IV<br>Drug: Dexamethasone<br>* Administered orally<br>|
| Experimental: 300 mg Tabalumab+BTZ IV+Dex<br>Cohort 2. 300 mg tabalumab (LY2127399) IV on day 1 of each cycle, each cycle is 21 days. BTZ, 1.3 mg/m^2, IV on days 1, 4, 8, 11 of Cycle 1-8, then on days 1, 8, 15, 22 from Cycle 9 onward. Oral dex, 20 mg/day, on day of and day after BTZ. | Biological: Tabalumab<br>* Administered IV<br>* Other names: LY2127399;Drug: Bortezomib IV<br>* Administered IV<br>Drug: Dexamethasone<br>* Administered orally<br>|
| Experimental: 300 mg Tabalumab+BTZ SC+Dex<br>Cohort 2-SC. 300 mg tabalumab (LY2127399)IV on day 1 of each cycle, each cycle is 21 days. BTZ, 1.3 mg/m^2, subcutaneously (SC) on days 1, 4, 8, 11 of Cycle 1-8, then on days 1, 8, 15, 22 from Cycle 9 onward. Oral dex, 20 mg/day, on day of and day after BTZ. Cohort 2-SC was added per protocol amendment in February 2013. | Biological: Tabalumab<br>* Administered IV<br>* Other names: LY2127399;Drug: Bortezomib SC<br>* Administered SC<br>Drug: Dexamethasone<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Drug Related Adverse Events (AEs) or Any Serious AEs | A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. | Baseline through 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Tabalumab (LY2127399) |  | Cycle 1, Day 1: 6 + or - hours after bortezomib (BTZ); Cycle 7, Day 1: immediately post BTZ dose and 2 hours after tabalumab | 
| Pharmacokinetics (PK): Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Plasma Concentration (AUC0-tlast) of Tabalumab (LY2127399) |  | Cycle 1, Day 1: 6 + or - hours after bortezomib (BTZ); Cycle 7, Day 1: immediately post BTZ dose and 2 hours after tabalumab | 
| Pharmacokinetics (PK): Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-∞) of Tabalumab (LY2127399) |  | Cycle 1, Day 1: 6 + or - hours after bortezomib (BTZ); Cycle 7, Day 1: immediately post BTZ dose and 2 hours after tabalumab | 
| Number of Participants With Tumor Response (Tumor Response Rate) | Stringent Complete Response- Complete response in addition to normal free light chain ration and no clonal cells in bone marrow. Complete Response- no monoclonal protein (mp) in blood, no serum or urine mp, less than 5% plasma cells in bone marrow. Very Good Partial Response-more than 90% decrease in mp and urine protein. Partial Response- over 50% decrease in serum mp. Stable Disease- less than 25 percent decrease of monoclonal protein. Progressive Disease- 25% increase compared to lowest value of serum mp, urine mp, no measurable mp. | Baseline to disease progression (up to 421 days) | 
| Duration of Response (DoR) | DoR is defined as the time from the date when the measurement criteria are met for CR, CRu, or PR (whichever status is recorded first) until the date of first observation of measured progressive disease. For responding participants who die without progressive disease (including death from study disease),DoR will be censored at the date of death. For responding participants not known to have died as of the data cut-off date and who do not have progressive disease, DoR will be censored at the last objective progression-free assessment date prior to the data cut-off date. | Time from Response until measured Progressive Disease (up to 455 days) | 
| Time to Progression (TTP) | TTP is defined as the time from the date of study enrollment to the date of objectively determined progressive disease. TTP will be censored at the date of the last objective progression free disease assessment. | Baseline to date of Progressive Disease (up to 455 days) | 
| Pharmacodynamics (PD): Change From Baseline in Absolute B-cell Count |  | Baseline through study completion (up to 455 days) | 
| Pharmacodynamics (PD): Change From Baseline in B-cell Subset Fractions | CD19+ peripheral B-cells counts are based on the percentage of total leukocyte population and absolute cell counts. | Baseline, Cycle 1 and Cycle 7: prior to first tabalumab dose. |