Prospective registration

A Phase 1B, Open-label, Multicenter Study Evaluating The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, And Preliminary Clinical Actvity of Cizutamig in Systemic Lupus Erythematosus

A Phase 1B, Open-label, Multicenter Study Evaluating The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, And Preliminary Clinical Actvity of Cizutamig in Systemic Lupus Erythematosus

Zeng Xiaofeng 

Zeng Xiaofeng 

No. 1 Shuaifu Garden, Dongcheng District, Beijing

No. 1 Shuaifu Garden, Dongcheng District, Beijing

Peking Union Medical College Hospital, Chinese Academy of Medical Sciences

Peking Union Medical College Hospital

Yes

Ethics Committee for Clinical Trials of Drugs at Peking Union Medical College Hospital Chinese Academy of Medical Sciences

Dong Yue

No. 1 Shuaifu Garden, Dongcheng District, Beijing

Peking Union Medical College Hospital

No. 1 Shuaifu Garden, Dongcheng District, Beijing

Candid Therapeutics LTD.

Systemic Lupus Erythematosus

Interventional study

1

Single arm 

Primary objective: To evaluate the safety and tolerability of Cizutamig. Secondary objective: To characterize the pharmacokinetics (PK) of Cizutamig in blood. Exploratory objectives: To evaluate the pharmacodynamics (PD) of Cizutamig To evaluate the disease-related biomarkers To evaluate the immunogenicity of Cizutamig To evaluate the clinical efficacy activity of Cizutamig

Patients are eligible for inclusion in the study only if all of the following criteria are met: 1. Aged between 18 and 75 years at the time of signing the informed consent form (ICF); 2. Diagnosis of systemic lupus erythematosus according to the 2019 American College of Rheumatology (ACR) and European Alliance of Association for Rheumatology (EULAR) classification criteria (Aringer et al, 2019); 3. Patients suspected of having lupus nephritis (e.g., proteinuria) must be screened as described in Section 5.1.1 to determine if they are eligible for inclusion in the study as SLE patients with active LN; 4. At screening, patients meet at least two of the following criteria, one of which must be anti-double-stranded deoxyribonucleic acid (anti-dsDNA) positive or anti-Smith antibody: a. Anti-double-stranded DNA antibodies; b. Anti-Smith antibodies; c. Antinuclear antibody (ANA) titer>=1:80; 5. Active SLE: SLEDAI-2K total score >=6 and SLEDAI-2K clinical score >=4 at screening; 6. The patient has a poor response to treatment as judged by the investigator, defined as using any of the following treatments at any time point before screening for at least 3 months, but lacks clinical efficacy or intolerance: antimalarials, mycophenolatemofetil MMF, azathioprine, cyclophosphamide, methotrexate (MTX), leflunomide, tacrolimus, vocyclosporine, cyclosporine, belinumab, terituximab, B Cell-depleting therapies (eg, rituximab, orizolizumab, inipilimab, ofalimumab), aniluzumab, and/or tetracycline; 7. Stable use of any of the following conventional therapies (alone or in combination) through study day D1: a. Methotrexate <=25 mg/week with stable medication >= 10 weeks prior to screening; b. Hydroxychloroquine <=400 mg/day and has been on stable medication for >=10 weeks prior to screening; c. Chloroquine <=250 mg/day, on stable medication >= 10 weeks prior to screening; d. Leflunomide <=20 mg/day and on stable medication >= 10 weeks prior to screening; Oral prednisone <=15 mg/day or equivalent dose until >= 2 weeks prior to screening; 8. Any of the following stable medications (alone or in combination) must be discontinued for >=1 week prior to study day D1: a. azathioprine: no more than 2 mg/kg/day at a dose ≥ 10 weeks prior to screening; b. Mycophenolate mofetil: >= 10 weeks prior to screening at a dose not exceeding 3 g/day; c. Mycopheno sodium: >= 10 weeks prior to screening at a dose not exceeding 2.16 g/day; d. Tacrolimus: >= 10 weeks prior to screening according to local standard of care regimen; e. Volosporine: >=10 weeks prior to screening according to local standard of care regimen; f. Cyclosporine: >= 10 weeks prior to screening according to local standard of care regimen. 5.1.1. Additional inclusion criteria for SLE patients with concomitant active LN 1. Active, biopsy-proven hypertrophic ulcerative nephritis type III or IV according to the 2018 International Society of Nephrology/Society of Renal Pathology criteria a. Biopsy must be performed within 1 year prior to or during screening b. Allow the incorporation of V-shapes 2. Proteinuria (24-hour urine protein>=0.75 g/24 hours or urine protein-to-creatinine ratio [UPCR]>=0.75 mg/mg) in a 24-hour urine sample after at least 3 months of treatment with one or more of the following conventional immunosuppressive therapies at any time prior to screening: azathioprine, MMF/mycophenome sodium, cyclophosphamide, calcineurin inhibitors, belinumab, terituximab, and/or anti-CD20 monoclonal antibodies; 3. Stable use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for at least 4 weeks prior to screening;

Patients who meet any of the following exclusion criteria must be excluded from the study: 1. Laboratory indicators at screening: a. Peripheral B cell count<=15 / mL b. IgG<=600 mg/ dL c. Hematology i. Absolute neutrophil count <=1.0×10^9/L (<=1.0×10^3/mL or <=1.0 GI/L) ii. Platelet count <=75×10^9/L (<=75×10^3mL or <=75 GI/L) iii. Hemoglobin level <=90 g/L iv. Lymphocyte count< 500/mL (<0.50×10^3/mL or <0.50 GI/L) d. Blood biochemistry i. ALT and AST levels >=2 times ULN ii. Total bilirubin level and alkaline phosphatase > 2 times ULN (or total bilirubin > 2.5 times ULN for patients with Gilbert's syndrome) e. Estimated glomerular filtration rate (estimated glomerular) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula filtration rate,eGFR)<=60 mL/min/1.73m^2; (If during screening, the original value due to laboratory error is deemed incorrect, a repeat assessment may be performed to confirm eligibility) 2. Patients will be excluded if they are known to have any of the following conditions: a. Any known HIV infection or positive for HIV type 1 or 2 antibodies at screening; b. Positive hepatitis B surface antigen (HBsAg). Patients who are positive for hepatitis B core antibody (HBcAb) must be tested for hepatitis B virus deoxyribonucleic acid (HBV-DNA) to determine their status; If HBV-DNA is positive, the patient should be excluded; If HBV-DNA is negative, the patient can participate in the study; c. Patients with positive hepatitis C antibody must be tested for hepatitis C ribonucleic acid (HCV RNA); If HCV RNA is also positive, the patient should be excluded; If HCV RNA is negative, the patient can participate in the study; d. Active tuberculosis (TB) or lack of documentation of completion of active tuberculosis treatment. If the tuberculosis test (QuantiFERON? -TB Gold Test or T-SPOT) is positive, the patient may have a chest x-ray to rule out latent or active tuberculosis according to local guidelines/standard of care requirements. If the test result is positive and no active tuberculosis is found on chest X-ray, the patient may be allowed to enroll after providing proof of completion of active tuberculosis or latent tuberculosis treatment; ? If the test result is inconclusive, the site should repeat the test; ? A positive test result or two consecutive indeterminate results should be considered a positive result; ? The subsequent negative test result after the indeterminate test result shall be regarded as a negative test result; Occult tuberculosis patients ? Those who have a record of completing anti-tuberculosis therapy before participating in the study can participate in this study; ? Patients with no documented treatment will be considered screen-ineligible for screening; Active infection with novel coronavirus type 2 (SARS-CoV-2), influenza, or respiratory syncytial virus (RSV) confirmed by screening test and asymptomatic for at least 1 week prior to the first dose of cizutami or those who do not have fever and their symptoms improve after stopping antipyretics can be enrolled; f. Patients with confirmed or suspected symptoms and/or signs of infection, temperature of 38°C and above, or antimicrobial use within 1 week prior to the first dose of cizutami; g. Within 3 months prior to the first dose of cizutami, had any of the following infections: Severe infection (requiring hospitalization or systemic antibacterial ≥ for 2 weeks); Opportunistic infections (including but not limited to Pneumocystis pneumonia, cytomegalovirus, toxoplasmosis, histoplasmosis, herpes zoster, as defined in Winthrop et al, 2015); Note: Shingles is considered active infection and persistent until all blisters dry and crust; Recurrent infections (including but not limited to herpes simplex, shingles, recurrent cellulitis, chronic osteomyelitis); Note: For patients with recurrent non-serious infections (such as urinary tract infections), if it does not increase the risk of complications in the patient, it may be decided by the investigator whether to include the patient; 3. Is receiving or unable to discontinue any of the following exclusionary therapies [except as indicated as recommended for acute management of CRS or ICANS] (see Section 10.5 for details; Table 13): a. Use of any of the following medications within 1 week prior to the first dose of Cizutami: i. Anti-cytometabolic drugs: MMF/mycophenolate sodium, azathioprine; ii. Calcineurin inhibitors: cyclosporine, tacrolimus, volocosporine; b. Use of any of the following medications within 4 weeks prior to screening: i. Alkylating agent: cyclophosphamide; ii. Janus kinase (JAK) inhibitors, brutontyrosine kinase (BTK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors: including but not limited to tofacitinib, upatinib, baricitinib, deuterium cleoxitinib; iii. Complement C5 terminal inhibitors: including but not limited to eculizumab, relizumab, ziluzumab, zilucoplan; iv. plasmapheresis or IVIG; v. Traditional Chinese medicines and proprietary Chinese medicines used for autoimmune diseases: including but not limited to tripterygium polyglycosides and white peony total glycosides; c. Use of any of the following medications (including biosimilars) within 12 weeks prior to screening: i. Tumor necrosis factor (TNF) inhibitors: including but not limited to infliximab and adalimumab; ii. Anti-cytokines (IL-1, IL-6, IL-17, IL-12/23): including but not limited to anakinra, tocilizumab, secukinumab, ustekinumab, rosalizumab; iii. Anti-BAFF or anti-APRIL: including but not limited to belimumab, tetacept; iv. thalidomide or thalidomide derivatives; v. Neonatal fragment crystallizable receptor (FcRn) inhibitors: including but not limited to egatimab and rozelixizumab; d. Use of any of the following medications within 24 weeks prior to screening: i. CD19 inhibitors: including but not limited to inerolizumab; ii. CD20 inhibitors: including but not limited to rituximab, orrelizumab, and otuzumab; iii. Other cell-depleting therapies, anti-CD3, anti-CD4, anti-CD5; e. Receiving CAR-T or TCE therapy with any antigen or BCMA-targeting therapy at any time; f. Use of any approved immunosuppressive medication not listed here within 12 weeks or 5 half-lives (whichever is longer) prior to screening, unless approved by the Medical Monitor; g. Participation in any investigational trial involving non-biological agents within 4 weeks or 5 half-lives of investigational products (IPs), whichever is longer, prior to screening; h. Participation in any investigational trial involving a biologic agent within 12 weeks or 5 half-lives of the investigational medicinal product (IP), whichever is longer, prior to screening; 4. Have received live vaccines within 4 weeks prior to screening; 5. Presence of any concomitant autoimmune disease (including overlap syndrome) requiring systemic therapy other than the disease under study. Note: Concomitant Sj?gren's syndrome is allowed; 6. Active or known history of catastrophic anti-phospholipid syndrome (APS); 7. APS or thrombotic events (e.g., deep vein thrombosis, pulmonary embolism) that have not been adequately controlled by anticoagulation therapy, defined as anticoagulation therapy for less than 6 months and/or thrombotic events within 1 year prior to screening; 8. History of progressive multifocal leukoencephalopathy; 9. History of primary immunodeficiency (such as hypogammaglobulinemia) or hereditary deficiency of the complement system; 10. Central nervous system (CNS) diseases are as follows: a. History of any neurological disease that, in the opinion of the investigator, would increase the risk to the subject (including but not limited to stroke, epilepsy, central nervous system vasculitis, multiple sclerosis, optic neuritis, transverse myelitis, or acute or chronic demyelinating polyneuropathy, neurodegenerative disease); b. Current active severe neuropsychiatric/CNSSLE (including but not limited to encephalitis, cerebrovascular accident, or seizures) as assessed by a neurologist and rheumatologist at screening; 11. Presence of 1 or more significant intercurrent illnesses, including but not limited to the following, as judged by the investigator: a. Poorly controlled diabetes; b. Chronic kidney disease stage IIIb, IV, or V; c. Severe chronic lung disease (e.g., requiring supplemental oxygen therapy) or respiratory failure; d. Severe or uncontrolled cardiovascular disease requiring treatment, including any of the following: i. Heart failure of New York Heart Association Class III or IV cardiac function within 12 months prior to screening; ii. Unstable angina within 12 months prior to screening (even controlled with medication); iii. Myocardial infarction within 12 months prior to screening; iv. Pericardial tamponade within 6 months prior to screening; v. QT interval (Fridericia formula correction, QTcF) > after single electrocardiogram (ECG) correction at screening 480 ms; vi. Severe cardiac arrhythmias requiring medication (excluding atrial fibrillation or paroxysmal supraventricular tachycardia); vii. Uncontrolled hypertension; viii. Those who are implanted with a pacemaker and whose condition is unstable as judged by the investigator; 12. Diagnosis or history of malignancy within 5 years prior to screening, with the following exceptions: i. Basal cell carcinoma or squamous cell carcinoma of the skin that has been resected with no signs of metastasis, or ii. Adequately treated cervical cancer in situ with no signs of recurrence within 5 years prior to screening. 13. Severe psychiatric illness, alcohol or drug abuse, dementia, or any other condition that may impair the patient's ability to receive planned treatment or understand informed consent at the study site (as determined by local clinical practice); 14. Unable to comply with the requirements of the research protocol; 15. History of severe anaphylaxis or anaphylactic shock reaction caused by monoclonal antibody therapy (or recombinant antibody-associated fusion protein) or any component of Cizutamig; 16. History of severe allergic reaction or anaphylactic shock, or intolerance to prophylactic antimicrobials: acyclovir/valacyclovir (for the prevention of herpes simplex virus/varicella-zoster virus) and compound sulfamethoxazole/trimethoprim/dapsone/atorvaquone (for the prevention of Pneumocystis jirovei pneumonia); 17. History of organ transplantation or planned organ transplantation, as well as autologous or allogeneic hematopoietic stem cell transplantation or planned such transplantation during the study period (from screening to the patient's last visit); or patients who have had a corneal transplant within 12 weeks prior to screening; 18. Major surgery requiring general anesthesia within 12 weeks prior to screening, or major surgery planned or anticipated during the study period (from screening to the patient's last visit); 19. Any serious medical condition or abnormality in clinical laboratory tests that, in the judgment of the investigator or medical monitor, would prevent the patient from safely participating in and completing the study, or may affect compliance with the protocol or interpretation of the study results; 20. Women of childbearing potential (WOCBP) (as defined in Section 10.4.1): a. Pregnant or lactating women; b. Patient does not agree to the following, starting with informed consent until at least 12 weeks after the last dose: ? Donate eggs is prohibited; ? Use of two highly effective methods of contraception (see Section 10.4.2), including complete abstinence if consistent with the patient's usual lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation) and extracorporeal ejaculation are not acceptable methods of contraception. Note: If female patients are taking oral contraceptives, they should remain stable for at least 12 weeks prior to the first dose of Cizutamig, as Cizutamig-induced cytokines may enhance the adverse effects of oral contraceptives; It is the responsibility of the investigator to review the patient's medical history, menstrual history, and recent sexual history to reduce the risk of inclusion of patients with early undetected pregnancies; 21. Sexually active male patients should not participate in this study if they do not agree to the following from the time of informed consent until at least 12 weeks after the last dose: ? Do not donate sperm; ? If the sexual partner is a female of childbearing potential (as defined in section 10.4.1), two highly effective methods of contraception (see section 10.4.2) must be used, including complete abstinence (if consistent with the patient's usual lifestyle). Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation) and extracorporeal ejaculation are not contraceptives; 22. Individuals who are considered to belong to vulnerable groups (e.g. detainees).

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CRF;EDC