A Study of TAK-007 in Adults With Refractory Lupus Nephritis (LN) or Refractory Systemic Sclerosis (SSc)

The main aim of the trial is to learn how well adults with refractory lupus nephritis (LN) or refractory systemic sclerosis (SSc) tolerate TAK-007 and to check for side effects (adverse events).

Other aims are to learn how effective treatment with TAK-007 is in adults with refractory LN or refractory SSc, what effects TAK-007 has on the human body, and whether participants will produce antibodies against TAK-007.

The drug being tested in this trial is called TAK-007. TAK-007 is being tested to treat people with refractory LN or refractory SSc. This trial will look at the safety and tolerability of TAK-007.

The trial will enroll approximately 26 participants. Participants will receive a single dose or multiple doses of TAK-007, which is an anti-CD19 chimeric antigen receptor natural killer cell (CD19 CAR-NK) therapy.

Participants with refractory LN will be treated with 3 days of intravenous (IV) lymphodepleting chemotherapy (LDC) and then after a gap of at least 2 days, a single IV dose of TAK-007 on Day 1. For participants with refractory SSc the trial has 2 parts. In Part 1, participants with refractory SSc will be treated with 3 days of IV LDC and then after a gap of at least 2 days, a single IV dose (Part 1a - single dose) or three IV doses (Part 1b - multiple doses) of TAK-007. Based on the data of Part 1, Part 2 (expansion) may be initiated in participants with refractory SSc to further evaluate the impact of LDC followed by single dose or multiple doses of TAK-007.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is approximately 24 months.

Eligibility Criteria:
Inclusion Criteria for LN Cohort:

1. The participant must have a diagnosis of SLE fulfilling European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria.
2. The participant must have a histologically proven glomerulonephritis (proliferative LN class III or IV, with or without the presence of class V, according to 2018 International Society of Nephrology/Renal Pathology Society \[ISN/RPS\] criteria).
3. The participant must be positive for ANA at screening or by documented medical history, and at least one of the following autoantibodies at screening: anti-dsDNA or anti-Smith (Sm) antibody.
4. The participant has had an inadequate response, defined as failure to improve within 12 weeks, based on investigator discretion, to at least 2 standard-of-care treatments for SLE (including glucocorticoids and immunosuppressive agents) OR at least 1 biologic treatment for SLE.
5. The participant has a SLEDAI-2K total score ≥6.

   Inclusion Criteria for SSc Cohort:
6. The participant must have a diagnosis of SSc fulfilling EULAR/ACR 2013 classification criteria.
7. The participant must have an early disease: 5 years or less of disease duration since first non-Raynaud's sign or symptom.
8. The participant must have evidence for presence of Interstitial Lung Disease (ILD) on HRCT imaging.
9. The participant must have active disease.
10. Positive for ANA (by immunofluorescent assay \[IFA\] with a titer ≥1:80) at screening or by documented medical history.
11. Lack of response or insufficient response (based on investigator discretion), to adequate doses of at least one of the following treatments used for at least 4 months: cyclophosphamide, methotrexate, mycophenolate (MMF)/mycophenolic acid, nintedanib, rituximab, or tocilizumab. Intolerance is not considered an insufficient response.

    Inclusion Criteria for LN and SSc Cohorts:
12. The participant must have adequate bone marrow function.
13. The participant must have adequate renal, hepatic, cardiac, and pulmonary function.
14. The participant is willing and able to understand and fully comply with trial procedures and requirements in the opinion of the investigator.
15. The participant has provided informed consent and any required privacy authorization before the initiation of any trial procedures.
16. The participant must be aged 18 to 75 years (inclusive) at the time of consent.
17. Participants with female reproductive anatomy must be:

    1. postmenopausal for at least 1 year before the screening visit, OR
    2. surgically sterile for at least 6 weeks, OR
    3. if the participant is of childbearing potential, must:

    i. Agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through at least 24 months following TAK-007 administration OR ii. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (periodic abstinence \[for example, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female and male condoms should not be used together AND iii. Agree not to donate an egg or eggs (ova) or breastfeed a baby during the trial and until at least 24 months following TAK-007 administration.
18. Participants with male reproductive anatomy, even if surgically sterilized (that is, status post vasectomy), must:

    1. Agree to practice effective barrier contraception from the time of signing the informed consent through at least 6 months following TAK-007 administration, or
    2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (periodic abstinence \[for example, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception), and
    3. Agree not to donate sperm during the trial and at least 6 months following TAK-007 administration.

Exclusion Criteria for LN Cohort:

1. The participant has a history of drug-induced SLE.
2. The participant has a current diagnosis of active or unstable neuropsychiatric lupus (e.g., cerebritis, cerebrovascular accident, and seizures). However, participants with mononeuritis multiplex or polyneuropathy can be included in the study.
3. The participant has a history of catastrophic antiphospholipid syndrome or saddle embolism (antiphospholipid syndrome adequately controlled by anticoagulant therapy for at least 3 months is acceptable).
4. The participant has a history or current diagnosis of other autoimmune diseases or current inflammatory joint or skin disease other than SLE that, in the opinion of the investigator and per sponsor assessment, could interfere with the inflammatory arthritis or skin assessments and confound the disease activity assessments.

   Exclusion Criteria for SSc Cohort:
5. The participant has ppFVC ≤45% or DLCO ≤40% or requiring supplemental oxygen at screening.
6. The participant has pulmonary arterial hypertension requiring active treatment.
7. The participant has anti-centromere antibody.
8. The participant has a history of severe scleroderma renal crisis OR scleroderma renal crisis within 6 months prior to Day 1.
9. The participant has obstructive pulmonary disease (pre-bronchodilator forced expiratory volume in 1 second (FEV1)/FVC \<0.7)
10. The participant has significant emphysema on screening HRCT, based on qualitative investigator assessment (extent of emphysema exceeds extent of ILD).
11. The participant has a history or current diagnosis of other systemic autoimmune diseases or current inflammatory joint or skin disease other than SSc that, in the opinion of the investigator and per sponsor assessment, could interfere with the trial assessments and confound the disease activity assessments.
12. The participant has actively bleeding gastric antral vascular ectasia
13. The participant has severe SSc-related lower gastrointestinal involvement requiring nutrition via percutaneous endoscopic gastrostomy/percutaneous endoscopic jejunostomy (PEG/PEJ) tube or parental nutrition.

    Exclusion Criteria for Both LN and SSc Cohorts:
14. The participant has any clinically significant medical condition, evidence of an unstable clinical condition (for example, cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, or immunologic), or vital signs/physical/laboratory/electrocardiogram (ECG) abnormality that would, in the opinion of the investigator and per sponsor assessment, put the participant at undue risk or interfere with interpretation of trial results.
15. The participant has a history of active infection (for example, coronavirus disease 2019 \[COVID-19\], influenza) or febrile illness within 7 days before enrollment.
16. Viral diseases:

    1. The participant is positive for hepatitis C virus (HCV) antibody and has a positive confirmatory test result for HCV ribonucleic acid \[RNA\] (nucleic acid test or polymerase chain reaction \[PCR\]).
    2. The participant is positive for hepatitis B surface antigen, hepatitis B virus (HBV) deoxyribonucleic acid (DNA), or hepatitis B core antibody.
    3. The participant has a history of human immunodeficiency virus (HIV) infection or has positive serology for HIV.
17. The participant has a history of significant chronic or recurrent bacterial disease, including but not limited to chronic pyelonephritis or cystitis, chronic bronchitis/pneumonitis, osteomyelitis, chronic skin ulcerations/infections or fungal infections, or latent tuberculosis infection.
18. The participant has a known or suspected allergy to TAK-007, or any of its components, or to cyclophosphamide or fludarabine.
19. The participant is unable to comply with the restrictions and prohibited treatments and/or discontinuation requirements.
20. The participant has given greater than 500 mL of blood or plasma within 30 days of screening (during a clinical trial or at a blood bank donation) or plans to donate blood during the course of the trial.
21. The participant is compulsorily detained for treatment of either a psychiatric or physical (for example, infectious disease) illness.