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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Galapagos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

14 Nov 2023 → ongoing

Decision date (initial)

2023-01-31

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of the Phase I part of the study is to evaluate the safety of GLPG5301 and determine the RP2D.
The primary objective of the Phase II part of the study is to evaluate the efficacy of GLPG5301, as measured by the objective response (OR).

Secondary objectives 6

1. Evaluate safety of GLPG5301
2. Evaluate efficacy of GLPG5301
3. Evaluate GLPG5301 pharmacokinetics
4. Evaluate GLPG5301 pharmacodynamics
5. Evaluate feasibility of GLPG5301 manufacturing in subjects with RRMM
6. Evaluate health-related QoL

Conditions and MedDRA coding

relapsed/refractory Multiple Myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Signed informed consent form
2. Age ≥ 18 years at the time of signing ICF
3. Multiple myeloma diagnosis according to the IMWG diagnostic criteria
4. 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
5. 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
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
7. 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
8. 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)
9. Women of childbearing potential must have a negative serum pregnancy test at screening and prior to the first dose of lymphodepleting chemotherapy
10. 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).

Exclusion criteria 13

1. 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
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.
3. 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
4. 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
5. 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
6. 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
7. 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.
8. 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.)
9. Vaccinated with live attenuated vaccine ≤ 6 weeks prior to the start of lymphodepleting chemotherapy
10. 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
11. Pregnant or nursing women, or planning to become pregnant within 12 months after GLPG5301 infusion
12. 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.
13. Subjects with a body weight less than 50 kg

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I dose-escalation phase: Incidence of (serious) adverse events ([S]Aes), Dose-limiting toxicities (DLTs) until Day 28
2. Phase II dose-expansion phase: Objective response (OR) until 2 years post GLPG5301 infusion per International Myeloma Working Group (IMWG) criteria

Secondary endpoints 13

1. Type, frequency and severity of (S)AEs (including AEs of special interest [AESI]) and clinically significant laboratory abnormalities
2. Best overall response (BOR) until 2 years post GLPG5301 infusion per IMWG criteria
3. Complete response (CR) until 2 years post GLPG5301 infusion per IMWG criteria
4. Progression-free survival (PFS)
5. Duration of response (DOR)
6. Overall survival (OS)
7. Minimal Residual Disease (MRD)
8. Soluble BCMA (sBCMA) levels
9. Time to Response (TTR), in subjects with a response
10. Levels of GLPG5301 in blood at peak and over time
11. Levels of chemokines and cytokines in serum over time
12. Number of successfully manufactured GLPG5301 products within the predefined release specifications
13. Change from baseline in measurement of health-related QoL as assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EQ-5D-5L, and EORTC QLC-MY20

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Galapagos

Sponsor organisation

Galapagos

Address

Generaal De Wittelaan L11 A3

City

Mechelen

Postcode

2800

Country

Belgium

Scientific contact point

Organisation

Galapagos

Contact name

Marte Liefaard

Public contact point

Organisation

Galapagos

Contact name

Marte Liefaard

Third parties 11

Locations

2 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 45 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications