An open label, phase I/II study investigating the safety and efficacy of the bispecific T-cell engaging antibody cizutamig (BCMAxCD3) in patients with immune-mediated inflammatory diseases – the SPLENDID Trial

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. Severe infection requiring hospitalization within the last two weeks. b. Any known human immunodeficiency virus (HIV) infection or positive HIV-1 or -2 antibody at screening c. 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. d. 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. e. 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 chimeric antigen receptor (CAR)-T or TCE therapy directed at any antigen or BCMA-targeted therapy at any time

Other illness

• Life-threatening allergies, hypersensitivity, or intolerance to cizutamig or its excipients or tocilizumab
• Malignancy in the last 5 years before screening (except 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 and need for supplemental oxygen

Lab values

• ANC < 500/µl, hemoglobin < 6/dl, absolute CD3+T cell count < 500/µl at screening
• Any condition, including the presence of laboratory abnormalities, which places the participants at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study, including active infections and within 1 week of completing anti-infective treatment, 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: e.g., 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: e.g., but not limited to tofacitinib, upadacitinib, baricitinib, deucravacitinib e. Complement inhibitors: e.g., 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: e.g., but not limited to infliximab, adalimumab or anti-cytokine (IL-1, IL-6, IL-17, IL-12/23): e.g., but not limited to anakinra, tocilizumab, secukinumab, ustekinumab, risankizumab i. Anti-B-cell activating factor (BAFF) or anti-a proliferation inducing ligand (APRIL): e.g., but not limited to belimumab, telitacicept j. Thalidomide or thalidomide derivatives k. CD19 inhibitor: e.g., but not limited to inebilizumab l. CD20 inhibitors: e.g., but not limited to rituximab, ocrelizumab, obinutuzumab m. Other cell depleting therapy, anti-CD3, anti-CD4, anti-CD5

Age

• Participants who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent

Other

• Pregnancy or lactation
• Females who are intending to conceive during the study
• Participants who possibly are dependent on the sponsor, the Principal Investigator or Investigator (e.g. family members)
• Patients who are institutionalized by court order or regulatory action
• Subjects participating in another clinical trial with an investigational medicinal product or medical device (there must be at least 3 months since the last IMP administration before this trial)
• Patients with known selective IgA deficiency
• IgG level below 4g/l at screening
• Inability to taper glucocorticoids to a maximun of 20mg prednisolone equivalent per day until enrolment

• Written informed consent and data protection declaration obtained prior to the initiation of any protocol required procedures
• Disease specific inclusion criteria (RA): a. Fulfilment of the 2010 ACR/EULAR classification criteria for RA b. Rheumatoid factor (RF) and/or ACPA positivity at screening c. Disease Activity Score DAS28-CRP>3.2 at screening d. Tender joint count (TJC) ≥ 3/68 and swollen joint count (SJC) ≥ 3/66 at screening e. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least one conventional DMARD and at least two tsDMARD/bDMARDs with different mechanisms
• Willing and able to comply to study procedures and study protocol
• Age ≥ 18 years at time of consent
• 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) throughout the trial
• 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. If they take oral contraceptives, the patients must also agree to use two other acceptable methods for contraception (e.g. spermicide and condom) during the trial.
• Updated vaccination record according to the Standing Committee on Vaccination (STIKO) recommendations for immunocompromised patients
• Disease specific inclusion criteria (SSC): a. Fulfillment of the 2013 ACR/EULAR classification criteria for SSc b. Positivity for at least one SSc-specific or associated antibody c. Diffuse cutaneous disease d. Severe disease defined as at least one of the following: i. Skin disease with screening mRSS ≥ 10 AND skin disease progression by ≥ 3 mRSS points or involvement of 1 new body area, or mRSS increase ≥ 2 units in 1 body area within the last 6 months and/or new tendon friction rubs ii. SSc-associated interstitial lung disease with either reduction of FVC of ≥ 5% and/or reduction of DLCO of ≥ 10% within the last 12 months before screening and/or presence of ILD with signs of alveolitis on HRCT with FVC < 85% iii. SSc-associated cardiac involvement with Troponin T elevation e. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least two of the following treatments with different mechanisms: glucocorticoids, methotrexate, azathioprine, mycophenolate mofetil, tocilizumab, rituximab, cyclophosphamide, tacrolimus, cyclosporine, nintedanib, hydroxychloroquine
• Disease specific inclusion criteria (IIM): a. Diagnosis of IIMs including DM, PM (including antibody-positive immune-mediated necrotizing myopathy [IMNM]), anti-synthetase syndrome according to the 2017 American College of Rheumatology [ACR]/European Alliance of Associations for Rheumatology [EULAR] classification criteria (including probable or definite diagnosis; > 55%) b. Positivity for at least one myositis specific or associated antibody c. Severe, active disease defined as at least one of the following: i. Myositis with • Recent (within the last 6 months) evidence of myositis in muscle biopsy and/or muscle MRI and/or EMG and/or PET/CT • AND/OR at least two of the following: Manual Muscle Testing-8 (MMT-8) score ≤142; extra-muscular activity ≥2 cm; health Assessment Questionnaire ≥0.25; at least one muscle enzyme >1.5 times upper limit of normal; VAS of patient global assessment ≥ 2 cm; VAS of physician global assessment ≥ 2cm ii. IIM-associated interstitial lung disease with reduction of FVC of ≥ 5% and/or reduction of DLCO of ≥ 10% within the last 12 months and/or presence of ILD with signs of alveolitis on HRCT with FVC < 85% d. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least two of the following treatments with different mechanisms: glucocorticoids, methotrexate, azathioprine, mycophenolate mofetil, rituximab, cyclophosphamide, intravenous immunoglobulins, tacrolimus, cyclosporin A, nintedanib, janus kinase inhibitors, hydroxychloroquine
• Disease specific inclusion criteria (pSjD): a. Fulfillment of the 2016 ACR/EULAR classification criteria for SjD b. Positivity for SSA antibodies in serum c. Moderate to severe disease defined as ESSDAI and/or ESSPRI ≥ 5 d. Failure (defined as inadequate response after at least 3 months of therapy or intolerance) of at least two of the following treatments with different mechanisms: glucocorticoids, hydroxychloroquine, methotrexate, azathioprine, leflunomide, rituximab, abatacept, belimumab, tacrolimus, cyclosporine A, mycophenolate mofetil, cyclophosphamide, intravenous immunoglobulins.