Open-label, Multi-center, Phase I/II Study to Assess Safety, Disease Progression and Cellular Kinetics Following YTB323 Administration in Participants With Non-active Progressive Multiple Sclerosis (PMS)

Официальное название

An Open-label, Multi-center, Phase I/II Study to Assess Safety, Disease Progression, and Cellular Kinetics Following YTB323 Administration in Participants With Non-active Progressive Multiple Sclerosis (PMS)

Обзор

This is an open-label, multi-center, non-confirmatory study to assess the safety, disease progression, and cellular kinetics following YTB323 administration to 28 participants with non-active Progressive Multiple Sclerosis (PMS). The study design utilizes an ascending single dose design consisting of 3 sentinel cohorts followed by an expansion cohort.

Подробное описание

All participants in this study will receive YTB323. Both the participant and the study doctor will know the participant is getting YTB323. Participants will be given one dose of YTB323. Different groups of participants may receive a higher dose of YTB323, if proven to be safe for every participant at the lower dose. Participants are in this study for 2 years and will be followed for an additional 13 years in a long-term follow up study. The main question this trial is designed to answer: Is YTB323 treatment safe for participants with progressive MS?

Вмешательства

• Биопрепарат rapcabtagene autoleucel (YTB323)
  CAR-T cell suspension for intravenous infusion

Первичные конечные точки

• Number of participants with dose limiting toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs) [Срок оценки: Day 1 through Year 2]

Вторичные конечные точки (12)

• Measure of Disability: Expanded Disability Status Scale (EDSS). [Срок оценки: Day 1 through Year 2]
• Measure of Disability: Short Form Health Survey (SF-36 v2) [Срок оценки: Day 1 through Year 2]
• Measure of Disability: Timed 25 Foot Walk (T25FW) [Срок оценки: Day 1 through Year 2]
• Measure of Disability: 9 Hole Peg Test (9HPT) [Срок оценки: Day 1 through Year 2]
• Measure of Disability: Symbol Digit Modalities Test (SDMT) [Срок оценки: Day 1 through Year 2]
• Modified Fatigue Impact Scale (MFIS) [Срок оценки: Day 1 through Year 2]
• Whole Blood Pharmacokinetics (PK) of YTB323 - CMAX [Срок оценки: Day 1 through Year 2]
• Whole Blood Pharmacokinetics (PK) of YTB323 - AUC [Срок оценки: Day 1 Through Year 2]
• Whole Blood Pharmacokinetics (PK) of YTB323 - Tmax [Срок оценки: Day 1 Through Year 2]
• Whole Blood Pharmacokinetics (PK) of YTB323 - Clast [Срок оценки: Day 1 Through Year 2]
• Whole Blood Pharmacokinetics (PK) of YTB323 - Tlast [Срок оценки: Day 1 through Year 2]
• Humoral Immunogenicity of YTB323 [Срок оценки: Day 1 through Year 2]

Критерии участия

Критерии включения

• Male or female participants 18 to 60 years (inclusive) at screening.
• Signed informed consent must be obtained prior to participation in the study.
• Able to communicate well with the investigator, to understand and comply with the requirements of the study including:

• Able to undergo lumbar puncture (LP), blood draws, tolerate brain and spinal MRI, and able to participate and tolerate all study procedures at study visits.
• Diagnosis of SPMS or PPMS according to the 2017 McDonald diagnostic criteria (Thompson et al 2018) as confirmed at screening visit.
• Less than 15 years (inclusive) from onset of first MS symptoms as determined by the investigator during screening.
• Ambulatory Patients (EDSS 3 to 6.5 inclusive) at screening.
• Evidence of recent (within 24 months) disease progression of ≥1.00 on the EDSS scale.
• No relapse in the last 24 months at screening.
• No Gd-enhancing lesion on brain or spinal cord MRI at screening.
• Participants must receive or be current on all recommended vaccinations according to institutional, local, or global guidelines for immunocompromised patients at least 6 weeks prior to lymphodepletion.

Критерии исключения

• Diagnosis of relapsing multiple sclerosis (RMS) or active PMS according to the 2017 revision of the McDonald diagnostic criteria (Thompson et al 2018) at screening.
• History of, or current, clinically significant CNS disease except MS (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy, history of seizures or epilepsy) or neurological disorders which may mimic MS at screening.
• Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, New York Heart Association Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 6 months prior to or during screening).
• Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or neurological symptoms consistent with PML prior to or during screening.
• Clinically significant, active, opportunistic, chronic or recurrent infection (including positive for hepatitis B or hepatitis C) confirmed by clinical evidence, imaging, or positive laboratory tests one month prior to leukapheresis.
• Have donated blood or experienced a loss of blood > 400 mL within 3 months prior screening, or longer if required by local regulations.
• Any prior stem cell therapy or organ transplantation or gene therapy.
• Any contraindications to LP, including but not limited to:

• Known or suspected structural abnormality of the lumbar spine that, in the opinion of the Investigator, may interfere with the performance of the LP, or increase the risk of the procedure for the participant.
• Presence of risk for increased or uncontrolled bleeding (including but not limited to vascular abnormalities or neoplasms at or near the LP site, disorders of the coagulation cascade, platelet function, or platelet count).
• Participants on anticoagulants (e.g., warfarin) or antiplatelets \[except for low-dose aspirin (100 mg/day or lower) and low-dose nonsteroidal anti-inflammatory drugs such as ibuprofen (600 mg/day or lower) which are allowed\], are not eligible to participate.
• Not willing or able to have MRI scans as per protocol e.g. due to claustrophobia, or absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator).
• Pregnant or nursing (lactating) women.
• Past surgical history of splenectomy.
• Evidence of active or latent tuberculosis (TB) infection by QuantiFERON® TB-Gold assay (or equivalent) performed at Screening by central lab. In case of unclear or indeterminate test results, the Investigator should consult with an infectious disease expert to exclude the diagnosis of active or latent TB infection and document this in the source data. Participant should be excluded if they have any signs of active TB observed in available lung imaging (e.g., X-ray or HRCT).
• Any psychiatric, pulmonary (including, history of or active severe respiratory disease, including Chronic Obstructive Pulmonary Disease, interstitial lung disease or pulmonary fibrosis), renal, hepatic, endocrine, metabolic (e.g. severe hypoproteinemia due to nephrotic syndrome), hematological disorders or gastrointestinal disease that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant, prior to or during screening.
• Grade 2 or higher thromboembolic event in the past 4 weeks prior to or during Screening or evidence of disorders of coagulation or platelet function including subjects that require chronic use of anticoagulation or antiplatelet drugs (please refer to the key exclusion criteria no. 8 for the exceptions).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 4 центра

• Novartis Investigative Site — Bron
• Novartis Investigative Site — Montpellier
• Novartis Investigative Site — Nancy
• Novartis Investigative Site — Rennes

Германия · 3 центра

• Novartis Investigative Site — Essen
• Novartis Investigative Site — Mainz
• Novartis Investigative Site — Ulm

Испания · 3 центра

• Novartis Investigative Site — Barcelona
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Málaga

Швейцария · 3 центра

• Novartis Investigative Site — Bern
• Novartis Investigative Site — Lausanne
• Novartis Investigative Site — Zurich

Австралия · 2 центра

• Novartis Investigative Site — Darlinghurst
• Novartis Investigative Site — Melbourne

Италия · 2 центра

• Novartis Investigative Site — Genova
• Novartis Investigative Site — Milan

Канада · 1 центр

• Novartis Investigative Site — Québec

Идентификаторы

NCT: NCT06675864 · CYTB323r12101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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