A Study of Tabalumab (LY2127399) in Participants With Previously Treated Multiple Myeloma (MM)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate an investigational drug called tabalumab in participants with Multiple Myeloma (MM) who have tried at least one other therapy in the past. Tabalumab will be given in combination with standard doses of two other drugs that are often used to treat MM. Study doctors will collect information about the effectiveness and side effects of this therapy.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Tabalumab in Combination With Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Placebo
* Drug: Dexamethasone
* Drug: Bortezomib
* Biological: Tabalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have symptomatic and/or progressive MM that was previously treated with at least 1 and no more than 3 prior lines of therapy Have measurable disease Have given written informed consent prior to any study-specific procedures Have adequate organ function Treatment with prior autologous transplant is permitted Exclusion Criteria: Are enrolled in or discontinued from a clinical trial of any drug or device within 21 days prior to the first dose of assigned study treatment Have had less than a minimal response or have had progressive disease within 60 days of most recent therapy with a proteasome inhibitor Plan to proceed to autologous transplant for consolidation after participation in this trial Have an active infection or ongoing treatment for systemic infection (ongoing treatment does not include prophylactic anti-infectives),, chest x-ray suggestive of tuberculosis, or history/risk of chronic/latent infection that may reactivate in the presence of study therapy Have any of the following: positive test results for human immunodeficiency virus (HIV) positive test for hepatitis B, 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) positive test results for hepatitis C virus (HCV), defined as positive for hepatitis C antibody (HepCAb) AND confirmed positive via the hepatitis C recombinant immunoblot assay Have had significant allergy to human/humanized monoclonal antibodies that, in the opinion of the investigator, poses an unacceptable risk to the participants Have known hypersensitivity or contraindication to any of the study therapies or excipients Prior allogeneic hematopoietic stem cell transplant Prior therapy with experimental agents targeting B-cell activating factor (BAFF), including LY2127399 Have corrected QT (QTc) interval >500 millisecond (msec) on baseline 12-lead electrocardiogram (ECG) Have Waldenstrom's macroglobulinemia History of malignancy with adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer, are eligible regardless of the time of diagnosis/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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg Tabalumab+Dexamethasone (Dex)+Bortezomib (BTZ)<br>Tabalumab 100 milligram (mg) administered once intravenously (IV) over 30 minutes on Day 1 every 21 days for 8 cycles. Dexamethasone 20 mg administered once orally on Days 1, 2, 4, 5, 8, 9, 11 and 12 every 21 days for 8 cycles. Bortezomib 1.3 milligram per square meter (mg/m^2) administered once subcutaneously (SQ) on Days 1, 4, 8 and 11 every 21 days for a minimum 8 cycles. All treatment may continue past 8 cycles. | Drug: Dexamethasone<br>* Administered orally<br>Drug: Bortezomib<br>* Administered SQ<br>Biological: Tabalumab<br>* Administered IV<br>* Other names: LY2127399;|
| Experimental: 300 mg Tabalumab+Dexamethasone+Bortezomib<br>Tabalumab 300 mg administered once IV over 30 minutes on Day 1 every 21 days for 8 cycles. Dexamethasone 20 mg administered orally on Days 1, 2, 4, 5, 8, 9, 11 and 12 every 21 days for a minimum 8 cycles. Bortezomib 1.3 mg/m^2 administered once SQ on Days 1, 4, 8 and 11 every 21 days for 8 cycles. All treatment may continue past 8 cycles. | Drug: Dexamethasone<br>* Administered orally<br>Drug: Bortezomib<br>* Administered SQ<br>Biological: Tabalumab<br>* Administered IV<br>* Other names: LY2127399;|
| Placebo Comparator: Placebo Comparator: Placebo + Dexamethasone + Bortezomib<br>Placebo administered once IV on Day 1 every 21 days for 8 cycles. Dexamethasone 20 mg administered once orally on Days 1, 2, 4, 5, 8, 9, 11 and 12 every 21 days for a minimum 8 cycles. Bortezomib 1.3 mg/m^2 administered once SQ on Days 1, 4, 8 and 11 every 21 days for 8 cycles. All treatment may continue past 8 cycles. | Drug: Placebo<br>* Administered IV<br>Drug: Dexamethasone<br>* Administered orally<br>Drug: Bortezomib<br>* Administered SQ<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from date of first dose to the first observation of disease progression or death due to any cause. If a participant does not have a complete baseline disease assessment, then the PFS time is censored at the enrollment date, regardless of whether or not objectively determined disease progression (Increase of > 25% from lowest response in serum M component, urine M component, bone marrow plasma cell percentage, development of bone lesions) or death has been observed for the participant. If a participant is not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time is censored at the last complete objective progression-free disease assessment date. | Baseline up to Objective Disease Progression or Death From Any Cause (assessed up to 9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is the duration from enrollment to death from any cause. For participants who were alive, overall survival was censored at the last contact. | Baseline to Death From Any Cause (assessed up to 19 months) | 
| Time to First Skeletal-Related Event (SRE) | Time to first SRE is defined as time from randomization to any one of the following related to multiple myeloma: New Pathological Fracture, Spinal Cord Compression, Surgery to the Bone, Radiation to the Bone collected until participant death, study closure or lost to follow up. Participants not known to have had an SRE at the time of the analysis were censored at the date of their last complete documented assessment for SRE. | Baseline to Date of First Skeletal Related Event (assessed up to 19 months) | 
| Number of Participants With >30% Reduction in Brief Pain Inventory (BPI) - Worst Pain Score | BPI is assessed by 7 questions rated 0 for no pain and higher numbers indicated more pain. | Baseline through End of Treatment (19 months) | 
| Time to Progression (TTP) | Time to progression is defined as the time from the date of randomization to the date of first observed objective progression or death due to study disease. Time to progression will be censored as for PFS for those participants not known to have progressed or that died from other causes. | Baseline to Objective Disease Progression or Death (assessed up to 9 months) | 
| Duration of Response (DoR) | DOR is measured by the International Myeloma Working Group Uniform Response Criteria: from the date of first evidence of a confirmed response to the date of objective progression or the date of death due to any cause, whichever is earlier. If a responder is not known to have died or have objective progression as of the data inclusion cutoff date, the DOR time will be censored at the last complete objective progression-free disease assessment date. Progressive disease is an increase of 25% from baseline in Serum M, Urine M, bone marrow plasma cell increase of 10 %, development of new bone lesions, development of new soft tissue plasmacytomas or bone lesions, hypercalcemia >11.5 milligrams per deciliter, decrease in hemoglobin of 2 grams per deciliter, rise in serum creatinine by 2 mg/deciliter. | Time from Response to Objective Disease Progression (assessed up to 38 months) | 
| Time to Next Treatment (TNT) | TNT is defined as the time from the date of randomization to the date of initiation of the first poststudy treatment course of anticancer therapy or death from any cause. Time to next treatment will be censored at the date of the last visit for participant who did not initiate additional anticancer therapy. | Baseline to Initiation of New Cancer Treatment or Death From Any Cause (18 Months) | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Tabalumab | Maximum Concentration (Cmax) of Tabalumab. | Cycle (C)1 Day (D)1: Predose, 3O minutes, 2 hours Postdose; C1 D4, 8, 11: Predose, (D11 only, 30 minutes Postdose); C2 and C6-C10 D1: Predose and immediately Postdose; C2 D 4, 8, 11: Anytime | 
| PK: Time to Maximum Plasma Concentration (Tmax) of Tabalumab |  | C1 D1: Predose, 3O minutes, 2 hours Postdose; C1 D4, 8, 11: Predose, (D11 only, 30 minutes Postdose); C2 and C6-C10 D1: Predose and immediately Postdose; C2 D 4, 8, 11: Anytime | 
| PK: Area Under the Curve Over the Dosing Interval (AUC-T) for Tabalumab |  | C1 D1: Predose, 3O minutes, 2 hours Postdose; C1 D4, 8, 11: Predose, (D11 only, 30 minutes Postdose); C2 and C6-C10 D1: Predose and immediately Postdose; C2 D 4, 8, 11: Anytime | 
| Number of Participants Developing Anti-tabalumab Antibodies |  | Baseline through Cycle 8 | 
| Participants With Best Overall Response (BOR) in Each Category | Stringent Complete Response-Complete Response and 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 Objective Disease Progression or Initiation of New Cancer Treatment (28 Months) | 
| Number of Participants With a Given Best Objective Myeloma Response (Quality of Response [QoR]) | Response categories in order of decreasing quality are: Stringent Complete Response(sCR),Complete Response(CR), Very Good Partial Response(VGPR),Partial Response(PR),Minimal Response(MR),Stable Disease(SD), or Progressive Disease(PD), according to the International Uniform Response Criteria for Multiple Myeloma.SCR:normal free light chain ration and no clonal cells in bone marrow;CR-no monoclonal protein(mp) in blood, no serum/urine,<5% plasma cells in bone marrow; VGPR-more than 90% decrease in mp and urine protein; PR->50% decrease in serum MP;SD-<25% decrease in mp; PD-25% increase compared to lowest value of serum mp, urine mp and no measurable mp. | Baseline to Objective Disease Progression or Initiation of New Cancer Treatment (up to 28 Months) | 
| Overall Response Rate (ORR) | Overall Response Rate (ORR) is the percentage of participants that had a response. | Baseline to Objective Disease Progression or Initiation of New Cancer Treatment (28 Months) |