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



Status:Terminated
Conditions:Lupus, Nephrology
Therapuetic Areas:Immunology / Infectious Diseases, Nephrology / Urology
Healthy:No
Age Range:18 - 75
Updated:1/31/2018
Start Date:July 9, 2014
End Date:January 15, 2018

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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

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.

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 determination
of the 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) will be recruited into the 0.5 mg dose group (Cohort
A), at least 5 participants (4:1) in the 2.0 mg dose group (Cohort B), 8 participants (6:2)
in the 3.0 mg dose group (Cohort C), and 8 participants (6:2) 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 a 28-days cycle, for 3 cycles. PK samples will be collected Predose on Days 1, 8 and 15.
Cycle 1 - Postdose Day 1 at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 168 hours. Cycle 2 - Postdose
Day 15 at 168 hours. Cycle 3 - Postdose on Day 15 following the third dose, samples will be
collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 168 and 312 hours . The starting dose in Cohort
1 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.

Inclusion Criteria:

1. In the opinion of the investigator, is capable of understanding and complying with
protocol requirements.

2. 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.

3. Is female or male and aged 18 to 75 years, inclusive.

4. 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.

5. Has a definite diagnosis of lupus nephritis (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).

1. If no biopsy was done within 2 year of Screening Visit, biopsy can be done during
the screening period as a study procedure.

2. Co-existence of classes is permitted.

6. Has a renal biopsy demonstrating either ISN/RPS or WHO class V or class V with class 2
nephritis with a UPCR of >3 or the subject 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 World Health Organization (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.

7. 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).

8. 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
mg/day of prednisone may be allowed to the study reviewed by the adjudication
committee and approved by the medical monitor; however, the steroid dose should be
tapered.

9. Male participants who are sexually active with women of child bearing potential
(WOCBP), even if surgically sterilized (ie, 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.

10. 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.

11. 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
Cohort C or D (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.

12. Must be receiving Standard of Care (SOC) treatment with an immunosuppressant drug for
the treatment of LN (eg, mycophenolate mofetil, mycophenolic acid or azathioprine.

Exclusion Criteria:

1. 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.

2. Has received ixazomib , bortezomib, or another proteasome inhibitor in a previous
clinical study or as a therapeutic agent.

3. 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 (eg, spouse, parent, child, sibling), or may consent under duress.

4. Has an autoimmune disease other than SLE as their main diagnosis.

5. Has drug-induced SLE.

6. Has severe, active central nervous system (CNS) lupus (British Isles Lupus Assessment
Group (BILAG) A or B).

7. Has an estimated glomerular filtration rate (eGFR) of <30 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.

8. Has a severe acute infectious disease (eg, untreated active tuberculosis (TB), acute
viral hepatitis, HIV), untreated latent TB, or infections requiring IV anti-microbial
treatment within 2 months preceding the Screening Visit.

9. 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.

10. Has one of the following laboratory test values:

1. IgG<75% of LLN

2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the
central laboratory's ULN

3. 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).

4. Platelets <75,000/mm^3

5. Neutrophils <1500/ mm3 or > 11,000/ mm^3

6. Hemoglobin <8 g/dL

7. Positive for Hepatitis B Surface Antigen.

8. Positive for Hepatitis C antibody.

11. 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.

12. 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.

13. 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.

14. 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.

15. Is taking excluded medications.

16. 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.

17. Has been treated with cyclophosphamide within 4 weeks of the Screening Visit.

18. Has been treated with > 3 g/day of mycophenolate mofetil within 4 weeks of the
Screening Visit.

19. Has been treated with belimumab, abatacept or tocilizumab within 3 months of the
Screening Visit.

20. Has been treated with eprazutumab, alemtuzumab, rituximab or other cell depleting
biological agents within 6 months of the Screening Visit.

21. 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.
We found this trial at
13
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Charleston, South Carolina 29412
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