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Trial record 1 of 2 for:    MLN9708_101
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Safety, Tolerability and Pharmacokinetics of Multiple Rising Doses of Ixazomib in Lupus Nephritis

This study is currently recruiting participants.
Verified June 2017 by Takeda
Sponsor:
ClinicalTrials.gov Identifier:
NCT02176486
First Posted: June 27, 2014
Last Update Posted: June 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Takeda
  Purpose
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.

Condition Intervention Phase
Lupus Nephritis Drug: Ixazomib Drug: Placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Percentage of Participants with at Least 1 Grade ≥2 Treatment Emergent Adverse Event (TEAE) According to Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: Day 168 after first dose ]
    A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug (AE start date greater than or equal to [≥] first dose date) and within 30 days after receiving the last dose of study drug (AE start date - last dose date less than or equal to [≤] 30). A TEAE may also be a pre-treatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug, which increases in intensity after the start of dosing.

  • Percentage of Participants with at Least 1 Serious Adverse Event (SAE) [ Time Frame: 198 days after first dose ]
    A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.

  • Percentage of Participants with at Least 1 Adverse Event Leading to Discontinuation of Investigational Study Medication [ Time Frame: 168 Days after first dose ]
    Withdrawal due to an AE will occur if the participant experiences an AE that requires early termination because continued participation imposes an unacceptable risk to the participant's health or the participant is unwilling to continue because of the AE.

  • Percentage of Participants with at Least 1 Markedly Abnormal Laboratory Criteria for Hematologic Parameters [ Time Frame: 168 Days after first dose ]
    The percentage of participants with any markedly abnormal hematology laboratory parameters.


Secondary Outcome Measures:
  • Change from Baseline in Urine Protein to Creatinine Ratio (UPCR) at Day 84 [ Time Frame: 84 days after first dose ]
  • Change from Baseline in Serum Creatinine (sCR) Level at Day 84 [ Time Frame: 84 days after first dose ]
  • Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Day 84 [ Time Frame: 84 days after first dose ]
  • Change from Baseline in Levels of Autoantibodies (Anti- Double-Stranded Deoxyribonucleic Acid [dsDNA]) and Complement (C3 and C4) [ Time Frame: 84 Days after first dose ]
  • Cmax: Maximum Observed Plasma Concentration [ Time Frame: Day 1 of Cycle 1 up to 168 hours post dose, and day 15 of Cycle 3 up to 312 hours post dose ]
  • Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) [ Time Frame: Day 1 of Cycle 1 up to 168 hours post dose, and day 15 of Cycle 3 up to 312 hours post dose ]
  • AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib [ Time Frame: Day 1 of Cycle 1 up to 168 hours post dose and Day 15 of Cycle 3 up to 312 hours post dose ]
  • Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose [ Time Frame: Day 1 of Cycle 1 up to 168 hours post dose and Day 15 of Cycle 3 up to 168 hours post dose ]

Estimated Enrollment: 40
Actual Study Start Date: July 9, 2014
Estimated Study Completion Date: June 8, 2018
Estimated Primary Completion Date: June 8, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A: Ixazomib 0.5 milligram (mg)
Ixazomib 0.5 mg, capsules, orally, once, on Day 1, 8 and 15 in a 28-day cycles, Cycles 1 through 3.
Drug: Ixazomib
Ixazomib capsules
Other Name: MLN9708
Experimental: Cohort B: Ixazomib 2 mg
Ixazomib 2 mg, capsules, orally, once, on Day 1, 8 and 15 in a 28-day cycles, Cycles 1 through 3.
Drug: Ixazomib
Ixazomib capsules
Other Name: MLN9708
Experimental: Cohort C: Ixazomib 3 mg
Ixazomib 3 mg, capsules, orally, once, on Day 1, 8 and 15 in a 28-day cycles, Cycles 1 through 3.
Drug: Ixazomib
Ixazomib capsules
Other Name: MLN9708
Experimental: Cohort D: Ixazomib 4 mg
Ixazomib 4 mg, capsules, orally, once, on Day 1, 8 and 15 in a 28-day cycles, Cycles 1 through 3.
Drug: Ixazomib
Ixazomib capsules
Other Name: MLN9708
Placebo Comparator: Cohorts A through D: Placebo
Ixazomib placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle, Cycles 1 through 3.
Drug: Placebo
Ixazomib placebo-matching capsules

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 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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02176486


Contacts
Contact: Takeda Study Registration Call Center +1-877-825-3327 medicalinformation@tpna.com

  Show 35 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director Clinical Science Takeda
  More Information

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02176486     History of Changes
Other Study ID Numbers: MLN9708_101
U1111-1152-6999 ( Other Identifier: World Health Organization )
2014-000125-21 ( EudraCT Number )
First Submitted: June 25, 2014
First Posted: June 27, 2014
Last Update Posted: June 8, 2017
Last Verified: June 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda:
Drug therapy

Additional relevant MeSH terms:
Ixazomib
Nephritis
Lupus Nephritis
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Glycine
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs