Safety, Tolerability and Pharmacokinetics of Multiple Rising Doses of Ixazomib in Lupus Nephritis (LN)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to characterize the safety and tolerability of ixazomib when administered as multiple oral doses at escalating dose levels in participants with lupus nephritis.

Detailed Description
-----------------
The drug being tested in this study is called ixazomib. Ixazomib is being tested to find a safe and well tolerated dose in participants with lupus nephritis. This study will look at side effects and lab results in participants who take ixazomib, along with the characterization of its pharmacokinetics (PK). This study is designed as a randomized, sequential-panel, multiple rising dose study. The study will enroll approximately 40 participants. The study population will consist of 4 Cohorts. At least 5 participants (4:1 active:placebo) will be recruited into the 0.5 mg dose group (Cohort A), at least 5 participants (4:1 active:placebo) in the 2.0 mg dose group (Cohort B), 8 participants (6:2 active:placebo) in the 3.0 mg dose group (Cohort C), and 8 participants (6:2 active:placebo) in the 4.0 mg dose group (Cohort D). Participants in each Cohort will be asked to take one capsule on Days 1, 8 and 15 in 28-day cycle, for 3 cycles. PK samples will be collected to measure concentrations of ixazomib. The starting dose in Cohort A will be 0.5 mg followed by administrations of 2, 3 and 4 mg in subsequent cohorts. This multi-center trial will be conducted in the United States and Europe. The overall time to participate in this study is up to 196 days. Participants will make 19 visits to the clinic during the treatment period and will make follow-up visits monthly for 3 months for follow-up assessments.

Official Title
-----------------
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and Pharmacokinetic Study of Multiple Rising Doses of MLN9708 for the Treatment of Subjects With ISN / RPS Class III or IV Lupus Nephritis

Conditions
-----------------
Lupus Nephritis

Intervention / Treatment
-----------------
* Drug: Ixazomib
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In the opinion of the investigator, is capable of understanding and complying with protocol requirements. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written informed consent form and any required privacy authorization prior to the initiation of any study procedures. Is female or male and aged 18 to 75 years, inclusive. Has a diagnosis of systemic lupus erythematosus (SLE) defined by meeting either the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria or the American College of Rheumatology (ACR) criteria for the classification of SLE. The 4 criteria required by ACR classification are not required to be present at Screening for eligibility. Has a definite diagnosis of LN based on a kidney biopsy done within 2 year of the Screening Visit which demonstrated International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV or V changes [excluding Class III (C), IV-S (C) and IV-G (C)] or World Health Organization (WHO) 1982 classification Class III,IV or V(excluding Class IIIc and IVd). If no biopsy was done within 2 year of Screening Visit, biopsy can be done during the screening period as a study procedure. Co-existence of classes is permitted. Has a renal biopsy demonstrating either ISN/RPS or WHO class V or class V with class 2 nephritis with a UPCR of greater than (>) 3 or the participant has a renal biopsy demonstrating either active ISN/RPS or WHO class III or IV nephritis, defined by either one of the following criteria: a) A UPCR* of >=1.0 at Screening OR b) A UPCR* >0.5 at Screening and at least one of the following: i. Active urine sediment in the absence of infection or other cause within 3 months of screening, defined as at least one of the following: >=5 red blood cells (RBC) per high power field, not due to causes other than lupus nephritis. >=5 white blood cells (WBC) per high power field in the absence of infection. Presence of cellular casts. ii. The participant has increased levels (above upper limit of normal [ULN]) serum dsDNA autoantibodies at screening. iii. Low complement (either C3 or C4) at Screening (>= 25 percent [%] lower than lower limit of normal [LLN]). iv. Biopsy within 3 months prior to screening visit indicating active proliferative lupus glomerulonephritis ISN/RPS class III or IV changes [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 classification Class III or IV (excluding Class IIIc and IVd), with co-existing Class V permitted. Participants may be re-screened once for urinary sediment, proteinuria or complement levels within 2 weeks of the original screening visit. UPCR value for eligibility will be based on the average UPCR obtained from the 3 specimens collected during screening. Has had an inadequate response, in the judgment of the Investigator, to at least 6 months of an immunosuppressive regimen including single or sequential use of at least one of the following: cyclophosphamide (CYC), mycophenolate mofetil (MMF), mycophenolic acid (MA), or azathioprine (AZA). If the participant is on glucocorticosteroids, must be on stable dose equivalent to 20 mg/day or less of prednisone for at least 2 weeks prior to first dose of study medication. Participant who are on a stable dose equivalent to >20 mg/day and <=30 milligram per day (mg/day) of prednisone may be allowed to the study if reviewed by the adjudication committee and approved by the medical monitor; however, the steroid dose should be tapered. Male participants who are sexually active with women of child bearing potential (WOCBP), even if surgically sterilized (that is, status post-vasectomy), must: a) Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug. Female participants who are of child bearing potential must: a) Agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug. This study permits the re-enrollment of a participant that has discontinued the study as a pre- treatment failure (ie, participant has not been randomized). If re-enrolled, the participant must be re-consented. * The re-enrollment of all participants who completed Cohort A and B is permitted to subsequent cohorts (2.0 mg and 3.0 mg dose cohorts) after completion of all cycles including the follow-up period if they had no drug-related adverse events greater than Grade 1, no adverse events greater than Grade 2, continue to meet all inclusion and exclusion criteria, and the Safety Review Committee has reviewed and approved enrollment of the subject into a higher dose cohort. Must be receiving Standard of Care (SOC) treatment with an immunosuppressant drug for the treatment of LN (example, MMF, MA or AZA). Exclusion Criteria: Has received any investigational compound within 30 days or 5 half-lives, whichever is the longer, prior to Screening or is currently participating in another interventional clinical study. Has received ixazomib, bortezomib, or another proteasome inhibitor in a previous clinical study or as a therapeutic agent. Is a sponsor employee, an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (example, spouse, parent, child, sibling), or may consent under duress. Has an autoimmune disease other than SLE as their main diagnosis. Has drug-induced SLE. Has severe, active central nervous system (CNS) lupus (British Isles Lupus Assessment Group [BILAG] A or B). Has an estimated eGFR of <30 milliliter per minute per 1.73 m^2 (mL/min/1.73m^2), or is on dialysis, or is expected to have a renal transplant within 1 year of randomization, or has had a renal transplant. Has a severe acute infectious disease (example, untreated active tuberculosis (TB), acute viral hepatitis, human immunodeficiency virus (HIV), untreated latent TB, or infections requiring IV anti-microbial treatment within 2 months preceding the Screening Visit. Has a history of a malignant disease (except successfully treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ) within 5 years prior to Screening. Has one of the following laboratory test values: IgG<75% of LLN Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the central laboratory's ULN Bilirubin >1.5 x ULN (participants with Gilbert Syndrome with a confirmed diagnosis and documented in the subject's medical record will not be excluded based on this criterion). Platelets <75,000 per cubic millimeter (/mm^3) Neutrophils <1500/ mm^3 or > 11,000/ mm^3 Hemoglobin <8 grams per deciliter (g/dL) Positive for Hepatitis B Surface Antigen. Positive for Hepatitis C antibody. Has a history of drug or alcohol abuse or dependence (as defined by Diagnostic and Statistical Manual of Mental Disorders, fourth Edition [DSM-IV]) within 1 year prior to the screening visit. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 3 months after participating in this study; or intending to donate ova during such time period. If male, the participant intends to donate sperm during the course of this study or for 90 days after the last dose. Male participants planning to father during clinical trial conduct or within 90 days after the last planned dose of trial treatment. Has moderate or severe liver disease (Child-Pugh B or C), and/or positive serological tests for hepatitis B (other than due to prior immunization) or hepatitis C. Is taking excluded medications. Has a history of clinically significant neuropathies of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 Grade 2 or higher. Has been treated with CYC within 4 weeks of the Screening Visit. Has been treated with > 3 g/day of MMF within 4 weeks of the Screening Visit. Has been treated with belimumab, abatacept or tocilizumab within 3 months of the Screening Visit. Has been treated with eprazutumab, alemtuzumab, rituximab or other cell depleting biological agents within 6 months of the Screening Visit. Current symptoms of severe, progressive, or uncontrolled non-SLE related renal, hepatic, hematological, gastrointestinal (including hypomotility and ulcerative/inflammatory conditions), pulmonary, cardiac, neurological, or cerebral disease, or other concomitant medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Ixazomib 0.5 milligram (mg)<br>Ixazomib 0.5 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. | Drug: Ixazomib<br>* Ixazomib capsules.<br>* Other names: MLN9708;|
| Experimental: Cohort B: Ixazomib 2 mg<br>Ixazomib 2 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. | Drug: Ixazomib<br>* Ixazomib capsules.<br>* Other names: MLN9708;|
| Experimental: Cohort C: Ixazomib 3 mg<br>Ixazomib 3 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. | Drug: Ixazomib<br>* Ixazomib capsules.<br>* Other names: MLN9708;|
| Experimental: Cohort D: Ixazomib 4 mg<br>Ixazomib 4 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. | Drug: Ixazomib<br>* Ixazomib capsules.<br>* Other names: MLN9708;|
| Placebo Comparator: Cohorts A through D: Placebo<br>Ixazomib placebo-matching capsules, orally, once on Days 1, 8 and 15 in 28-day cycle, Cycles 1 through 3. | Drug: Placebo<br>* Ixazomib placebo-matching capsules.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced at Least One Grade Greater Than or Equal to (>=) 2 Treatment Emergent Adverse Event (TEAE) |  | Baseline up to Day 101 (30 days after last dose of study drug) | 
| Percentage of Participants Who Experienced at Least One Treatment Emergent Serious Adverse Event (SAE) |  | Baseline up to Day 101 (30 days after last dose of study drug) | 
| Percentage of Participants Who Experienced at Least One AE Leading to Study Drug Discontinuation |  | Baseline up to Day 168 | 
| Percentage of Participants With at Least One Markedly Abnormal Value (MAV) for Hematologic Parameters |  | Baseline up to Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Day 84 |  | Baseline and Day 84 | 
| Change From Baseline in Serum Creatinine (sCR) Level at Day 84 |  | Baseline and Day 84 | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Day 84 |  | Baseline and Day 84 | 
| Change From Baseline in Levels of Autoantibodies (Anti-double-stranded Deoxyribonucleic Acid [dsDNA]) at Day 84 |  | Baseline and Day 84 | 
| Change From Baseline in Complement Protein C3 and C4 at Day 84 |  | Baseline and Day 84 | 
| Plasma Concentrations of Ixazomib at Each Scheduled Collection Time |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length is equal to [=] 28 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug Therapy