Phase 2 Multicohort Open-Label Study of Ciltacabtagene Autoleucel CAR-T Therapy Targeting BCMA in Multiple Myeloma Patients

The primary objective of this study is to evaluate the overall **minimal residual disease (MRD)** negative rate in subjects with **Multiple Myeloma** who receive JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA). Achieving MRD negativity is clinically significant as it is associated with improved long-term outcomes and survival rates in patients with multiple myeloma, indicating a deeper response to treatment.

The clinical trial involves a total of **114 participants** diagnosed with **Multiple Myeloma**, a hematologic malignancy. The study population includes both male and female subjects, encompassing an age range that includes adults and older adults. Participants were selected based on specific criteria related to their treatment history and disease status, as outlined in the study protocol. The trial includes individuals who have undergone various prior therapies, including proteasome inhibitors (PI), immunomodulatory drugs (IMiD), and anti-CD38 monoclonal antibodies, with some having received stem cell transplants. The study population is characterized by a measurable disease at screening, as defined by specific laboratory and imaging criteria. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial also considers lifestyle factors such as adherence to contraception guidelines for women of childbearing potential and men, as per the local global REVLIMID® pregnancy prevention program or equivalent local Risk Evaluation and Mitigation Strategy (REMS). The trial includes a vulnerable population, ensuring that ethical considerations are in place for their participation.

The clinical trial is designed as a **Phase 2**, multicohort, open-label study to evaluate the efficacy, safety, and pharmacokinetics/pharmacodynamics of JNJ-68284528 in adult participants with **multiple myeloma**. The primary objective is to assess the overall minimal residual disease (MRD) negative rate using next-generation sequencing or next-generation flow, as defined by the International Myeloma Working Group criteria. The trial is expected to run from February 13, 2020, to June 13, 2025, with participants being involved for varying durations depending on the treatment cohort they are assigned to.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as prior lines of therapy and measurable disease status. The trial includes multiple cohorts, each with distinct eligibility requirements, such as prior exposure to specific therapies or disease stage. Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected length of participant involvement varies, with treatment periods ranging from 1 to 112 weeks, depending on the specific medication regimen and cohort assignment. Conditions that may lead to early termination from the study include adverse events, disease progression, or withdrawal of consent. The trial employs a combination of oral and intravenous administration routes, with medications such as **lenalidomide**, **fludarabine**, **cyclophosphamide**, **dexamethasone**, **daratumumab**, **bortezomib**, and **ciltacabtagene autoleucel** being utilized in various combinations across the cohorts. The study is not classified as low intervention, indicating a more intensive monitoring and intervention approach.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Lenalidomide Accord** is provided in various dosages, including 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, all in the form of hard capsules. The active substance is **lenalidomide**, a chemical compound, administered orally. The treatment period for lenalidomide is up to 25 days, with the frequency and specific dosing schedule determined by the study protocol.

**Fludarabine** is utilized as a non-experimental treatment in the form of a powder for solution for injection. The active substance, fludarabine, is of chemical origin and is administered intravenously. The treatment period for fludarabine is up to 3 days, with dosing based on body surface area (mg/m²).

**Cyclophosphamide** is another non-experimental treatment, provided as a powder for solution for injection. The active substance, cyclophosphamide, is administered intravenously, with a treatment period of up to 3 days. Dosing is also based on body surface area (mg/m²).

**Dexamethasone** is administered in two forms: as 4 mg tablets (Dexamethason 4 mg JENAPHARM®) and as 2 mg tablets (Dexamethasone Tablets BP 2.0mg). The active substance, dexamethasone, is administered orally, with a treatment period of up to 112 days. The specific dosing schedule is outlined in the study protocol.

**Daratumumab** is provided under the product name JNJ-54767414, in the form of an injection. The active substance, daratumumab, is a protein of other origin, administered subcutaneously. The treatment period is up to 36 days, with dosing details specified in the protocol.

**Ciltacabtagene autoleucel** is administered as a dispersion for infusion under the product name JNJ-68284528. This is a cell therapy product, administered intravenously, with a treatment period of 1 day. The dosing is based on body weight (kg), and specific administration details are provided in the study protocol.

**Bortezomib** is provided as VELCADE 3.5 mg powder for solution for injection. The active substance, bortezomib, is administered subcutaneously, with a treatment period of up to 84 days. The dosing schedule is detailed in the study protocol.

Participant compliance with the dosing schedule is monitored throughout the study, ensuring adherence to the protocol. The study protocol provides detailed instructions on the administration and monitoring of each treatment, ensuring the safety and efficacy of the trial.

The efficacy of the clinical trial will be assessed by evaluating the overall **minimal residual disease (MRD)** negative rate in subjects receiving JNJ-68284528. The primary endpoint is the MRD negative rate at a threshold of 10^-5, as defined by the International Myeloma Working Group (IMWG) criteria. This will be measured using next-generation sequencing (NGS) or next-generation flow (NGF) techniques. The trial aims to determine the efficacy of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy, in subjects with multiple myeloma. The study is designed as a Phase 2, multicohort, open-label trial, focusing on the efficacy, safety, and pharmacokinetics/pharmacodynamics of the treatment.