Multiple Sclerosis, Multiple Sclerosis, Primary Progressive, Multiple Sclerosis, Secondary Progressive
Conditions
Keywords
KYV-101, autoimmune disease, anti-CD19 CAR-T therapy, cellular therapy
Brief summary
A Study of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Subjects with Non-relapsing and Progressive Forms of Multiple Sclerosis
Detailed description
Multiple Sclerosis (MS) is an immune-mediated neurodegenerative central nervous system disease that can lead to loss of vital neurologic function. The clinical course of MS from person to person is variable. Progressive Multiple Sclerosis (pMS) is marked by a history of neurologic worsening over time; and can occur following a prior history of defined relapses that has evolved to a non-relapsing state (previously termed "secondary progressive MS" (SPMS)) or from disease onset (termed "primary progressive MS" (PPMS)). There are now more than twenty FDA approved disease modifying therapies (DMTs) for MS in the United States. Most of these treatments have an approved FDA indication for relapsing disease. Several have a labeled indication for active secondary progressive MS, and only one has been FDA approved for primary progressive MS. There are no formally approved treatments for patients with non-relapsing progressive Multiple Sclerosis that is worsening, treatment refractory, and non-active as defined operationally by absence of relapse of magnetic resonance imaging evidence of inflammatory disease within the preceding two years. B cells play a central and multi-functional role in the immunopathogenesis of MS. B cells present antigen to T cells in stimulating a pro-inflammatory immune cascade, secrete pathogenic cytokines, moderate T cell and myeloid cell functions, form structural B cell meningeal follicles within the human central nervous system, act as reservoirs for Epstein-Barr virus (EBV) infection, and produce pathogenic antibodies upon evolution to plasma cells. CD19-targeted chimeric antigen receptor (CAR) T cells harness the ability of cytotoxic T cells to directly and specifically lyse target cells to effectively deplete B cells in the circulation and in lymphoid and potentially non-lymphoid tissues. KYV-101, a fully human anti-CD19 CAR T-cell therapy, will be investigated in adult subjects with non-relapsing and progressive forms of MS.
Interventions
BIOLOGICALKYV-101 anti-CD19 CAR-T cell therapy
KYV-101 anti-CD19 CAR-T cell therapy
Standard lymphodepletion regimen
Sponsors
Stanford University
Kyverna Therapeutics
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Patient is ≥ 18 years old, and ≤65 years of age, at time of screening visit. 2. Diagnosis of MS according to the 2017 McDonald Criteria. 3. Progressive MS by 2014 Lublin MS phenotypic criteria. 4. Presence of varicella-zoster virus (VZV) antibodies, or completion of at least one dose of the varicella zoster glycoprotein E (gE) Shingrix vaccine at least four weeks prior to treatment. 5. Presence of anti EBV antibodies. 6. Organ and Marrow Function * Absolute neutrophil count (ANC) ≥ 2000/uL. * Platelet count ≥ 150,000/uL. * Absolute lymphocyte count ≥ 1000/uL. * Serum immunoglobulin G (IgG) ≥ 500mg/dL. * Hemoglobin ≥ 9 g/dL. * Adequate renal, hepatic, pulmonary and cardiac function defined as: * Creatinine ≤ 2mg/dL or creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 60 mL/min. * Serum alanine transaminase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN). * Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome * Cardiac ejection fraction ≥ 40%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, and no clinically significant ECG findings. * Baseline oxygen saturation \> 94% on room air. 7. Testing for * Hepatitis B core antibody (HBc Ab) * Hepatitis C antibody (HCV Ab) * Hepatitis B surface antigen (Hep B surf. AG) * HIV 1\&2 Ab * Syphilis Screen * Human T-cell lymphotropic virus (HTLV) Ab I \& II * Nucleic acid test multiplex (NAT MPX) for HIV, HCV, HBV * Herpes Simplex Virus 1 \& 2 IgG panel * Varicella-Zoster (VZ) IgG * Cytomegalovirus (CMV) Total Ab Must be seronegative for HIV-1 RNA polymerase chain reaction (PCR); HIV 1 and HIV 2 Ab (antibody); HTLV-1 and HTLV-2 Ab; PCR+ or negative surface antigen for hepatitis B; negative for the Treponema pallidum antibody Syphilis screen; and negative for HIV-1 and hepatitis C by nucleic acid testing (NAT) within 40 days of apheresis procedures. 8. Females of childbearing potential have a negative serum or urine pregnancy test because of the potentially dangerous/unknown effects on the fetus. Females who have undergone hysterectomy or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential. 9. Contraception: Subjects of child-bearing or child-fathering potential must be willing to practice highly effective birth control from the time of enrollment on this study and for the entire study period which is 12 months after receiving the CAR T cell infusion. 10. Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial. 11. Adequate vital sign criterion with acceptable numerical ranges of: * Systolic Blood Pressure (mmHg) ≥ 100 and ≤ 150 * Diastolic Blood pressure (mmHg) ≥ 60 and ≤ 90 * To ensure subject safety and stability, any subject who is noted to have a BP \> 150/90 mm Hg should be stable on anti-hypertensive medications with repeated BP ≤150/90 for at least one month prior to enrollment in the study * Heart Rate ≥ 60 and ≤ 100 bpm * Oral Temperature ≤ 37.7 C/afebrile * Respiratory rate ≥ 12 and ≤ 20bpm
Exclusion criteria
1. History of neuromyelitis optica spectrum disorder (NMOSD) or MOG antibody associated disease (MOGAD). 2. Prior treatment with any investigational agent within 3 months, or 5 half-lives, whichever is longer. Agents authorized by the FDA for prevention or treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not considered investigational. 3. Initiation of any DMT between the completion of apheresis and start of lymphodepletion (LD) chemotherapy. The use of methylprednisolone for bridging therapy between apheresis and start of LD chemotherapy will be allowed. 4. History of CNS or spinal cord tumor, metabolic or infectious cause of myelopathy, genetically inherited progressive CNS disorder, sarcoidosis or non-MS progressive neurologic condition affecting ability to perform study assessments. 5. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS). 6. History of sickle cell anemia or other hemoglobinopathy. 7. Coagulation abnormalities defined by: international normalized ratio (INR) \> 1.5, prothrombin time (PT) \> 14 seconds, partial thromboplastin time (PTT) \> 45 seconds to the
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Frequency of dose limiting toxicities at each dose level | Up to 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs) including clinical tolerance and laboratory abnormalities | Up to 12 months | Clinical tolerance will be assessed with attention to cytokine release syndrome (CRS), Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) and other AE to be graded by CTCAE Version 5.0 |
| To characterize the pharmacokinetics (PK) | Up to 12 months | Levels of KYV-101 CAR-positive T cells in the blood and cerebrospinal fluid from treatment baseline to end of study |
| To characterize the pharmacodynamics (PD) | Up to 12 months | Levels of B cells in the blood from treatment baseline to end of study |
| To evaluate clinical response | Up to 12 months | Time from CD19 KYV CAR T cell infusion to a change in disability and walking score, as measured by the Kurtzke Expanded Disability Status Scale (EDSS) |
Countries
United States
Contacts
CONTACTMultiple Sclerosis and Neuroimmunology Study Team
PRINCIPAL_INVESTIGATORJeffrey Dunn, MD
Stanford University
Outcome results
None listed