An open label, phase I/II study investigating the safety and efficacy of a CD3/CD20 bispecific T-cell engager therapy in patients with active, treatment refractory, ANCA-IgG-positive associated vasculitis. The RENEWAL study

Prior treatment

• Requirement for immunization with live vaccine during the study period
• Patients will be excluded if they are known to have any of the following: a. Any known human immunodeficiency virus (HIV) infection or positive HIV-1 or -2 antibody at Screening b. Positive hepatitis B surface antigen (HBsAg). Patients with positive hepatitis B core antibody (HBcAb) must be tested for hepatitis B virus (HBV)-DNA to determine their status; if HBV-DNA is positive, patients should be excluded; if HBV-DNA is negative, the patient may participate in the study. c. Patients with positive hepatitis C virus (HCV) antibody must be tested for HCV ribonucleic acid (RNA); if HCV RNA is also positive, patients should be excluded; if HCV RNA is negative, the patient may participate in the study at the investigator’s discretion. d. Active tuberculosis (TB) or lack of documentation of completion of treatment for active TB. If the TB test (QuantiFERON® Gold Test) is positive, patients may be allowed to enroll if chest CT is negative for active TB and treatment according to local guidelines has been initiated or completed prior to enrollment. If the test result is indeterminate, the site should repeat the test. A positive test result or 2 successive indeterminate results should be considered as a positive result. An indeterminate test result followed by a negative test result should be considered as a negative test result.
• Prior CAR-T or TCE therapy directed at any antigen or BCMA-targeted therapy at any time

Other illness

• Known hypersensitivity to any drug components
• Malignancy in the last 5 years before screening (except adequately treated basal or squamous cell skin cancer
• Participants who have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results
• Severely impaired liver (Child Pugh C), cardiac or pulmonory (NYHA IV) function
• Life-threatening allergies, hypersensitivity, or intolerance to CND261 or its excipients or tocilizumab

Lab values

• ANC < 500/µl, ALC < 100/µl or hemoglobin < 6/dl, absolute CD3+T cell count < 100/µl at screening
• Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study, including active severe and uncontrolled infections within the last two weeks, neurologic conditions, primary immunodeficiency and history of splenectomy
• Receipt of or inability to discontinue any of the following excluded therapies at screening: a. Anti-metabolites: MMF/mycophenolate sodium, azathioprine, methotrexate b. Calcineurin inhibitors: eg, but not limited to cyclosporine, tacrolimus, voclosporin c. Alkylating agent: cyclophosphamide d. Janus kinase (JAK) inhibitors, Bruton tyrosine kinase (BTK) inhibitors, Tyrosine kinase 2 (TYK2) inhibitors: eg, but not limited to tofacitinib, upadacitinib, baricitinib, deucravacitinib e. Complement inhibitors: eg, but not limited to eculizumab, ravulizumab, zilucoplan, avacopan f. Plasmapheresis or intravenous immunoglobulin (IVIg) g. FcRn inhibitors: including but not limited to efartigimod, rozanolixizumab h. Any of the following (including biosimilars): Tumor necrosis factor (TNF) inhibitors: eg, but not limited to infliximab, adalimumab or anti-cytokine (IL-1, IL-6, IL-17, IL-12/23): eg, but not limited to anakinra, tocilizumab, secukinumab, ustekinumab, risankizumab i. Anti-B-cell activating factor (BAFF) or anti-a proliferation inducing ligand (APRIL): eg, but not limited to belimumab, telitacicept j. Thalidomide or thalidomide derivatives k. CD19 inhibitor: eg, but not limited to inebilizumab l. CD20 inhibitors: eg, but not limited to rituximab, ocrelizumab, obinutuzumab m. Other cell depleting therapy, anti-CD3, anti-CD4, anti-CD5

Other

• Participants who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent
• Participants who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g. family members)
• Participants who are institutionalized by order of court or public authority
• Participants participating in another clinical trial with an investigational medicinal product or medical device (at least 3 months since the last IMP administration before this trial)
• Pregnancy or lactation
• Females who are intending to conceive during their study participation

• Understand and voluntarily sign an informed consent form
• Male or female, age ≥ 18 years at time of consent
• Able to adhere to the study visits and protocol
• Fulfillment of EITHER both of the following: • 2022 ACR/EULAR classification criteria for granulomatosis with polyangiitis (GPA) • Anti-PR3 antibodies titer above the laboratory threshold for positivity at screening OR both of the following: • 2022 ACR/EULAR classification criteria for microscopic polyangiitis (MPA) • Anti-MPO antibodies above the laboratory threshold for positivity at screening
• A Birmingham Vasculitis Activity Score (BVAS) of at least 3 within 12 months before screening
• Insufficient response or intolerance to at least three months of treatment with at least two of the following therapies: rituximab, mycophenolate mofetil, azathioprin, methotrexate, cyclophosphamide, avacopan, glucocorticoids; or to at least six weeks of treatment with cyclophosphamide or plasmapheresis and rituximab combination therapy. Patients without prior rituximab treatment may also be included if treatment with rituximab is considered not advisable based on the investigator’s clinical judgment (e.g., due to contraindication, prior hypersensitivity, increased infection risk, or other medical or safety considerations
• Male participants unless surgically sterile, must agree to use two acceptable methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) until 12 months after dosing of the IMP
• Females of childbearing potential (FCBP) must have a negative serum pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index <1) starting from the time of signing the ICF and throughout the trial
• Updated vaccination record according to the STIKO recommendations for immunocompromised patients