KYV-101 for ANCA-associated vasculitis|Granulomatosis with polyangiitis (GPA)|Microscopic polyangiitis (MPA)

Inclusion criteria

• {"criterion_text":"- Understand and voluntarily sign an informed consent form\n- Additional criteria before leukapheresis: no evidence of a clinically significant active infection\n- Additional criteria before leukapheresis: negative urine pregnancy test in female patients\n- Additional criteria before leukapheresis: no clinically relevant abnormal findings on brain MRI, EEG, Echocardiogram or lung function test which would put the subject at undue risk when participating in this study\n- Additional criteria before lymphodepletion: no evidence of a clinically significant active infection\n- Additional criteria before lymphodepletion: eGFR > 30 ml/min/m2\n- Additional criteria before lymphodepletion: no acute central neurological toxicity\n- Additional criteria before lymphodepletion: negative urine pregnancy test in female patients\n- Additional criteria before lymphodepletion: notification of successful CAR T cell production by the manufacturer\n- Additional criteria before IMP administration: no evidence of a clinically significant active infection\n- Additional criteria before IMP administration: no acute central neurological toxicity\n- Male or female, age ≥ 18 and ≤ 75 years at time of consent\n- Able to adhere to the study visits and protocol\n- Fulfilment of •\tEITHER both of the following \t2022 ACR/EULAR classification criteria for granulomatosis with polyangiitis (GPA) \tdetectable anti-PR3 antibodies (≥ 20 AU/ml in CLIA) at screening •\tOR both of the following \t2022 ACR/EULAR classification criteria for microscopic polyangiitis (MPA) \tdetectable anti-MPO antibodies (≥ 10 AU/ml in CLIA) at screening\n- Active disease, defined as Clinical activity (BVAS ≥ 3) at screening\n- Insufficient response or intolerance/contraindication to glucocorticoids and to at least one of the following treatments: rituximab, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, avacopan. Insufficient response is defined as hav-ing disease activity based on the definition explained in the previous bullet point\n- Male subjects 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\n- Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl in-dex <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP\n- Updated vaccination record according to the STIKO recommendations for immuno-compromised patients"}

Exclusion criteria

• {"criterion_text":"- ANC < 500/µl, ALC < 100/µl or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl at screening\n- Known hypersensitivity to any drug components\n- Malignancy in the last 5 years before screening (except adequately treated basal or squamous cell skin cancer)\n- Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis,\n- Subjects who are younger than 18 years or are incapable to understand the aim, im-portance and consequences of the study and to give legal informed consent (accord-ing to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG),\n- 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 participa-tion or study agent administration, or may interfere with interpretation of results,\n- Subjects who possibly are dependent on the Sponsor, the Principal Investigator or In-vestigator (e.g. family members).\n- Subjects who are institutionalized by order of court or public authority,\n- Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial).\n- Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), or heart or pulmonary (NYHA IV, blood oxygenation < 92%) function\n- Clinically relevant rapidly progressive glomerulonephritis or pulmonary alveolar hem-orrhage\n- Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study\n- Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy)\n- History of bone marrow/ hematopoietic stem cell or solid organ transplantation\n- Any concomitant severe active infection, e.g. HIV, hepatitis B or C, SARS-CoV-2 (COVID-19), or active tuberculosis as defined by a positive Quantiferon TB-test. If presence of latent tuberculosis is established then treatment according to local guide-lines must have been initiated prior to enrollment\n- Pregnant or lactating females\n- Females who are intending to conceive during the study"}

Primary endpoints

• {"endpoint_text":"- Safety (Phase I): Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of Immune Cell Associated Neurotoxicity Syndrome (ICANS) within the first 4 weeks after anti-CD19 CAR T cell therapy.  AE and SAE due to IMP within the first 4 weeks.","definition_or_measurement_approach":"Incidence and grading of CRS and ICANS using severity grading scale (graded 0-4) within first 4 weeks; collection of AEs and SAEs due to IMP within first 4 weeks."}
• {"endpoint_text":"- Safety (Phase II): AE and SAE due to IMP throughout the whole study. All subjects will enter in an obligatory follow-up phase for evaluation of long-term safety lasting 15 years in total. Data will be registered in the EBMT registry after informed consent is obtained from the patients.","definition_or_measurement_approach":"Collection of AEs and SAEs due to IMP throughout study; long-term safety follow-up lasting 15 years with data registration in the EBMT registry after informed consent."}
• {"endpoint_text":"- Efficacy (Phase II): Percentage of AAV subjects (GPA) with normal anti-PR3 antibodies (< 20 AU/ml) and AAV subjects (MPA) with normal anti-MPO antibodies (< 10 AU/ml) at week 24.","definition_or_measurement_approach":"Proportion of subjects achieving anti-PR3 <20 AU/ml (GPA) or anti-MPO <10 AU/ml (MPA) measured at week 24."}

Secondary endpoints

• {"endpoint_text":"- Survival time without immunosuppression from week 9 to week 52","definition_or_measurement_approach":"Measurement of survival time off immunosuppression between week 9 and week 52."}
• {"endpoint_text":"- Time to relapse/flare from week 9 to week 52","definition_or_measurement_approach":"Time-to-event measurement of relapse/flare occurring between week 9 and week 52."}
• {"endpoint_text":"- Percentage of patients who reach EULAR response criteria (≥ 50% reduction of Birmingham Vasculitis Activity Score (BVAS) at week 12, 24 and 52) compared to baseline","definition_or_measurement_approach":"Proportion meeting ≥50% reduction in BVAS at weeks 12, 24 and 52 vs baseline."}
• {"endpoint_text":"- Percentage of patients who reach EULAR sustained remission criteria (Absence of typical signs, symptoms, or other features of active AAV) through week 52","definition_or_measurement_approach":"Proportion achieving absence of signs/symptoms of active AAV through week 52."}
• {"endpoint_text":"- Change of Vasculitis Damage Index (VDI) at week 12, 24 and 52 compared to baseline","definition_or_measurement_approach":"Change from baseline in VDI at weeks 12, 24 and 52."}
• {"endpoint_text":"- Change in Birmingham Vasculitis Activity Score (BVAS) at week 12, 24 and 52 compared to baseline","definition_or_measurement_approach":"Change from baseline in BVAS at weeks 12, 24 and 52."}
• {"endpoint_text":"- Number of flares through week 12, 24 and 52 weeks","definition_or_measurement_approach":"Count of flares recorded through weeks 12, 24 and 52."}
• {"endpoint_text":"- Percentage of subjects with normal anti-PR3 antibodies (< 20 U/ml) at week 12 and 52 (GPA).","definition_or_measurement_approach":"Proportion with anti-PR3 <20 U/ml at weeks 12 and 52 (GPA)."}
• {"endpoint_text":"- Percentage of subjects with normal anti-MPO antibodies (< 10 U/ml) at week 12 and 52 (MPA).","definition_or_measurement_approach":"Proportion with anti-MPO <10 U/ml at weeks 12 and 52 (MPA)."}
• {"endpoint_text":"- Duration of persistence of CAR T cells in the peripheral blood","definition_or_measurement_approach":"Measurement of duration of detectable CAR T cells in peripheral blood over time."}
• {"endpoint_text":"- Duration of B cell depletion in the peripheral blood","definition_or_measurement_approach":"Measurement of duration of peripheral blood B cell depletion."}
• {"endpoint_text":"- Expansion of CAR T cells in the patient over time","definition_or_measurement_approach":"Kinetics/measurement of CAR T cell expansion over time."}
• {"endpoint_text":"- Change in anti-PR3 antibodies over time (GPA)","definition_or_measurement_approach":"Longitudinal measurement of anti-PR3 antibody levels over predefined timepoints."}
• {"endpoint_text":"- Change in anti-MPO antibodies over time (MPA)","definition_or_measurement_approach":"Longitudinal measurement of anti-MPO antibody levels over predefined timepoints."}
• {"endpoint_text":"- Change in total IgG, IgG subclasses and IgA, IgM immunoglobulins over time","definition_or_measurement_approach":"Serial measurement of total IgG, IgG subclasses, IgA and IgM over time."}
• {"endpoint_text":"- Change in MPO (MPA) or PR3 (GPA) specific plasmablasts and B-cells","definition_or_measurement_approach":"Measurement of MPO/PR3-specific plasmablast and B-cell counts over time."}
• {"endpoint_text":"- Change in the number of plasmablasts, B cell and T cell numbers over time","definition_or_measurement_approach":"Serial measurement of plasmablast, B cell and T cell counts over time."}
• {"endpoint_text":"- Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)","definition_or_measurement_approach":"PtGA measured on a VAS 0-100 mm scale at scheduled visits."}
• {"endpoint_text":"- Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)","definition_or_measurement_approach":"PhGA measured on a VAS 0-100 mm scale at scheduled visits."}
• {"endpoint_text":"- European Quality of Life 5 Dimensions (EQ-5D)","definition_or_measurement_approach":"EQ-5D instrument administered per schedule."}
• {"endpoint_text":"- Short Form 36 (SF-36, quality of life questionnaire)","definition_or_measurement_approach":"SF-36 questionnaire administered per schedule."}
• {"endpoint_text":"- ANCA-associated vasculitis patient reported outcome (AAV-PRO)","definition_or_measurement_approach":"AAV-PRO patient-reported outcome instrument administered per schedule."}
• {"endpoint_text":"- To analyze the changes in B cell receptor repertoire","definition_or_measurement_approach":"Analysis of B cell receptor repertoire changes over time (methodology per protocol)."}
• {"endpoint_text":"- To evaluate the therapy-induced changes of B cell subsets","definition_or_measurement_approach":"Characterization of B cell subset changes over time."}
• {"endpoint_text":"- Characterizing B Cell and Plasma Cell Niches in Tissues","definition_or_measurement_approach":"Tissue analyses to characterize B cell and plasma cell niches (methodology per protocol)."}
• {"endpoint_text":"- To evaluate the therapy-induced alterations of T cell compartments","definition_or_measurement_approach":"Evaluation of therapy-induced changes in T cell compartments."}
• {"endpoint_text":"- To evaluate changes in kidney biopsy from baseline to week 52 (optional)","definition_or_measurement_approach":"Optional kidney biopsy comparison baseline vs week 52."}

Germany

Earliest CTIS Part Ii Submission Date

02-12-2024

Latest Decision Or Authorization Date

09-12-2024

Processing Time Days

7

Number Of Sites

1

Number Of Participants

8

Primary sponsor

Full Name

Charite Universitaetsmedizin Berlin KöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Universitaetsklinikum Erlangen AöR","duties_or_roles":"sponsorDuties code: 8","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Radiologie am Kudamm (vendor for radiology assessments)","duties_or_roles":"Radiology examinations (sponsorDuties code: 15)","organisation_type":"Health care"}
• {"country":"Germany","full_name":"Labor Berlin Charite Vivantes GmbH","duties_or_roles":"sponsorDuties code: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Charite Universitaetsmedizin Berlin KöR","duties_or_roles":"sponsorDuties codes: 1, 6","organisation_type":"Hospital/Clinic/Other health care facility"}