A phase I/II open label, multicenter study evaluating the feasibility, safety and efficacy of point-of-care manufactured antiBCMA CAR T cells (GLPG5301; BCMACP03) in subjects with relapsed/refractory Multiple Myeloma (RRMM)

Trial ID: 2022-500782-27-00
Protocol: CP0301-MM
Sponsor: Lakefront Biotherapeutics

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Diseases & Conditions

Plasma cell myeloma refractory

Objectives

The primary objective of this phase I/II open-label, multicenter study is to evaluate the **safety** of GLPG5301 and determine the recommended phase 2 dose (RP2D) during the Phase I part. In the Phase II part, the primary objective is to assess the **efficacy** of GLPG5301, as measured by the objective response (OR), in subjects with relapsed/refractory Multiple Myeloma (RRMM). These objectives are clinically relevant as they aim to establish the safety profile and therapeutic potential of GLPG5301, a point-of-care manufactured antiBCMA CAR T cell therapy, which could offer a novel treatment option for patients with RRMM.

Secondary objectives include: - Evaluating the **safety** of GLPG5301 - Assessing the **efficacy** of GLPG5301 - Analyzing the **pharmacokinetics** of GLPG5301 - Investigating the **pharmacodynamics** of GLPG5301 - Evaluating the feasibility of GLPG5301 manufacturing in subjects with RRMM - Assessing health-related quality of life (QoL). These secondary objectives provide a comprehensive understanding of the treatment's overall impact, including its biological behavior, production feasibility, and effect on patients' quality of life.

Participants

The clinical trial involves participants diagnosed with **relapsed/refractory Multiple Myeloma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a diagnosis of multiple myeloma according to the International Myeloma Working Group (IMWG) diagnostic criteria and must have relapsed or refractory disease after at least two lines of prior systemic therapy, including a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 antibody treatment. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate bone marrow, renal, hepatic, and pulmonary function are required, and women of childbearing potential must have a negative serum pregnancy test at screening. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed as a **phase I/II open-label, multicenter study** to evaluate the feasibility, safety, and efficacy of point-of-care manufactured antiBCMA CAR T cells, specifically GLPG5301, in subjects with **relapsed/refractory Multiple Myeloma**. The trial is structured to include both a dose-escalation phase (Phase I) and a dose-expansion phase (Phase II). The primary objective of Phase I is to assess the safety of GLPG5301 and determine the recommended Phase II dose (RP2D), while Phase II aims to evaluate the efficacy of GLPG5301, measured by the objective response (OR) according to the International Myeloma Working Group (IMWG) criteria. The trial is expected to conclude by February 2027, with recruitment having commenced in February 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history. The inclusion criteria require participants to have a diagnosis of multiple myeloma, be at least 18 years old, and have relapsed or refractory disease after at least two lines of prior systemic therapy. Following the screening, eligible participants will receive the investigational product, GLPG5301, via **intravenous infusion**. Subsequent follow-up visits will be scheduled to monitor safety and efficacy outcomes, including the incidence of adverse events and objective response rates. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last up to two years post-infusion.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The study will also monitor secondary endpoints such as progression-free survival, overall survival, and levels of GLPG5301 in the blood. The trial's design ensures rigorous monitoring and data collection to support the evaluation of GLPG5301's therapeutic potential in this patient population.

Treatment

The clinical trial involves the administration of the experimental medication **BCMACP03**, which is a **dispersion for infusion**. This investigational product is designed for use in subjects with relapsed/refractory **Multiple Myeloma**. BCMACP03 is a cell therapy product, specifically an anti-BCMA CAR T-cell therapy, which is manufactured at the point of care. The active substance, BCMACP03, is a structurally diverse substance categorized under cell therapy. The pharmaceutical form of BCMACP03 is a dispersion intended for intravenous infusion. The administration route is exclusively via **intravenous infusion**, and the frequency of administration will be determined based on the study protocol. The product is not formulated for pediatric use and is not classified as an orphan drug.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapies, placebo, or comparator treatments, as per the study design. However, specific details regarding these non-experimental treatments are not provided in the available data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The study aims to evaluate the feasibility, safety, and efficacy of BCMACP03, with the primary objective of determining the recommended Phase 2 dose (RP2D) and assessing the objective response in subjects.

Efficacy

The efficacy of the investigational product GLPG5301 in the clinical trial will be assessed primarily through the **Objective Response (OR)**, as defined by the International Myeloma Working Group (IMWG) criteria. This primary endpoint will be evaluated during the Phase II dose-expansion phase and will be measured until two years post-infusion of GLPG5301. Secondary efficacy endpoints include the Best Overall Response (BOR), Complete Response (CR), Progression-Free Survival (PFS), Duration of Response (DOR), Overall Survival (OS), and Minimal Residual Disease (MRD), all assessed per IMWG criteria. Additionally, soluble BCMA (sBCMA) levels, Time to Response (TTR) in subjects with a response, and levels of GLPG5301 in blood at peak and over time will be measured. The levels of chemokines and cytokines in serum over time will also be evaluated. The change from baseline in health-related quality of life (QoL) will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EQ-5D-5L, and EORTC QLC-MY20 instruments. These assessments will provide a comprehensive evaluation of the efficacy of GLPG5301 in subjects with relapsed/refractory Multiple Myeloma.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent form
Age ≥ 18 years at the time of signing ICF
Multiple myeloma diagnosis according to the IMWG diagnostic criteria
Relapsed or refractory disease after at least 2 lines of prior systemic therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and anti-CD38 antibody treatment, and relapsed or refractory to last line. Refractory is defined as documented evidence of PD by IMWG criteria on or within 60 days of the last regimen. Subjects who progressed within the previous 6 months and were nonresponsive (defined as failure to achieve minimal response) to the most recent line of treatment afterwards will be eligible for the study. Subject must have undergone at least 1 complete cycle of treatment for each line of therapy, unless PD was the best response to the line of therapy or if subject was ineligible for any of these agents Note: Induction with or without autologous hematopoietic stem cell transplant (HSCT), consolidation and maintenance therapy is considered a single line of therapy
Measurable disease at screening as defined by any one or more of the following criteria: • Serum M-protein level ≥ 0.5 g/dL • Urine M-protein level ≥ 200 mg/24 hours • Serum free light chain (FLC) level ≥ 10 mg/dL and abnormal serum FLC ratio
Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
Adequate bone marrow function defined as: •Hemoglobin ≥ 8 g/dL or ≥ 5 mmol/L (without prior RBC transfusion within 7 days before the laboratory test) •Absolute neutrophil count (ANC) ≥ 1x10^3/μLor ≥ 1.0 × 10^9/L (without granulocyte colony-stimulating factor [G-CSF] support within 7 days of the laboratory test or pegylated G-CSF support within 14 days of the laboratory test) •Platelet count ≥ 50x10^3/μL or ≥ 50 × 10^9/L, without prior platelet transfusion within 7 days before the laboratory test •Absolute lymphocyte count ≥ 300/μL or ≥ 0.3 × 10^9/L •Absolute number of CD3+ T cells ≥ 150/μL or ≥ 0.15 × 10^9/L
Adequate renal, hepatic, and pulmonary function defined as: •Creatinine clearance (Cockcroft Gault) ≥ 45 mL/min •Aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) •Alanine aminotransferase (ALT) ≤ 3 × ULN •Total bilirubin ≤ 2 x ULN. For subjects with Gilbert’s syndrome total bilirubin must be ≤3 × ULN. •Baseline oxygen saturation > 92% on room air. Subjects with dyspnea are eligible if their dyspnea is Grade ≤1, according to Common Terminology Criteria for Adverse Events (CTCAE)
Women of childbearing potential must have a negative serum pregnancy test at screening and prior to the first dose of lymphodepleting chemotherapy
Women of childbearing potential and all male subjects must agree to use highly effective methods of contraception (failure rate of < 1% per year when used consistently and correctly) and agree to remain on a highly effective method of contraception from the time of signing the ICF until at least 12 months after GLPG5301 infusion. Subjects must agree to not donate eggs or sperm during this period (Appendix 4).

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Exclusion Criteria

Any of the following: •AL Amyloidosis, Waldenström’s Macroglobulinemia, POEMS syndrome, Plasma Cell Leukemia •High tumor burden, defined as any of the following: clonal bone marrow plasma cell percentage≥80% in either the bone marrow aspirate or biopsy, serum M-protein ≥5g/dL, involved serum FLC ≥5000 mg/L, or total sum of the products of the maximal perpendicular diameters of measured extramedullary lesions (SPD) of >25 cm^2
Prior treatment: •Any BCMA-directed therapy •Any CAR T-cell therapy •Monoclonal antibody treatment for multiple myeloma within 21 days before leukapheresis and T-cell engagers within 3 months before leukapheresis •Cytotoxic therapy within 14 days before leukapheresis, alkylating agents within 6 weeks before leukapheresis, the alkylating agent melphalan flufenamide within 3 months prior to leukapheresis, the alkylating agent bendamustine within 6 months before leukapheresis •PI therapy within 14 days before leukapheresis •IMiD therapy within 7 days before leukapheresis •Other targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 14 days before leukapheresis or at least 5 half-lives, whichever is less •Radiotherapy within 8 weeks of leukapheresis •Allogeneic HSCT within 6 months before leukapheresis. Subjects who received an allogeneic transplant must have stopped all immunosuppressive medications for 6 weeks without signs of graft-versus-host disease. Subjects with active graft-versus-host disease are excluded •Autologous HSCT within 3 months before leukapheresis •Systemic corticosteroid therapy at a pharmacologic dose (> 30 mg/day of hydrocortisone or equivalent doses of other corticosteroids) is not allowed for 7 days prior to leukapheresis and within 72 hours prior to GLPG5301 infusion (if restarted) Note: Topical and inhaled corticosteroids in standard doses and physiologic replacement for subjects with adrenal insufficiency at a maximum of 30 mg/day hydrocortisone or equivalent doses of other corticosteroids are allowed at all times.
History of a primary malignancy other than multiple myeloma that requires intervention beyond surveillance or that has not been in remission for at least 3 years. The following are exempt from the 3-year limit •Adequately treated non-melanoma skin cancer without evidence of disease •Curatively treated localized prostate cancer (as per primary tumor [T], regional lymph nodes [N], distant metastases [M] TNM staging) without evidence of disease •Carcinoma in situ (e.g. cervix, bladder, breast) on biopsy or a squamous intraepithelial lesion on Papanicolaou (PAP) smear
Any subject with ongoing toxicity from any previous treatment that has not resolved to Grade 2 or better, and has not been specified in any other in- or exclusion criterion, should be discussed with the sponsor’s medical monitor
Clinically significant cardiac disease such as: •Myocardial infarction or coronary artery bypass graft within 6 months of screening •History of New York Heart Association Class III or IV congestive heart failure, ≤ 12 months prior to screening •Clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration, non-ischemic cardiomyopathy, or other clinically significant cardiac disease within 12 months of screening •Impaired cardiac function (left ventricular ejection fraction [LVEF] < 45%) and/or evidence of clinically significant and/or symptomatic pericardial effusion as assessed by echocardiogram or multigated acquisition [MUGA] performed ≤ 4 weeks prior to screening
Infection with human immunodeficiency virus (HIV)-1/2, hepatitis B virus (HBV) or hepatitis C virus (HCV). A history of hepatitis B or C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing
Systemic fungal, bacterial, viral, or other infection that is not controlled, defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment. If a subject is on active treatment for an infection, this needs to be discussed with the sponsor’s medical monitor.
Other medical contraindications: •Any significant medical condition, laboratory abnormality, or psychiatric illness that would in the opinion of the investigator or sponsor’s medical monitor place the subject at unacceptable risk during the study or prevent the subject from participating in the study and make it unlikely for the subject to complete all protocolrequired study visits or procedures (including follow-up visits) or confounds the ability to interpret data from the study •Any history or presence of clinically relevant central nervous system (CNS) pathology such as signs and symptoms of altered mental status, psychosis, dementia, neurocognitive, neurodegenerative or neuroinflammatory disorders, e.g. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis •Any presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, and severe brain injuries. When there is a previous history of such CNS pathology, the subject should be fully recovered at least 1 year prior to leukapheresis •Active autoimmune disease, or a history of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within 6 months prior to screening •Primary immunodeficiency •Contraindications to leukapheresis or inadequate venous access •Known allergy or hypersensitivity to any product (including its excipients) to be given to the subject as per study protocol (e.g. tocilizumab, all per study protocol described lymphodepleting chemotherapy options, dimethyl sulfoxide [DMSO], etc.)
Vaccinated with live attenuated vaccine ≤ 6 weeks prior to the start of lymphodepleting chemotherapy
Major surgery within 4 weeks of screening. In case surgery was longer ago, but subject is still in recovery, the subject should be discussed with the sponsor’s medical monitor
Pregnant or nursing women, or planning to become pregnant within 12 months after GLPG5301 infusion
Subjects who have had a venous thrombo-embolic event requiring anticoagulation and who meet any of the following criteria: a. Have been on a stable dose of anticoagulation for <1 month b. Have had Grade ≥ 2 hemorrhage in the past 6 weeks Note: Any subject who is on a therapeutic dosage of anticoagulant treatment should be discussed with the sponsor’s medical monitor before inclusion in the clinical study.
Subjects with a body weight less than 50 kg