A Study of Fully Human BCMA Chimeric Antigen Receptor Autologous T Cell Injection (CT103A) in the Treatment of Patients With Relapsed/Refractory Multiple Myeloma

A Phase Ib Clinical Study of Fully Human BCMA Chimeric Antigen Receptor Autologous T Cell Injection (CT103A) in the Treatment of Patients With Relapsed/Refractory Multiple Myeloma

It is a dose expansion, open-label, phase Ib study to evaluate the safety, efficacy, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of CT103A in patients with relapsed/refractory multiple myeloma.

A total of at least 12 subjects are planned to be enrolled in this study. Each subject will proceed through the following study periods:

• Screening
• Leukapheresis
• Bridging therapy (at the discretion of the investigator)
• Pre-lymphodepletion assessment
• Lymphodepleting chemotherapy
• Pre-infusion Assessment
• CT103A infusion (Day 0)
• 28-Day safety evaluation period
• Post-treatment follow-up period (Day 29 through year 2)

All the subjects will be followed for safety and efficacy until disease progression, initiation of subsequent anti-myeloma therapy, withdrawal, death, loss to follow-up, study completion, end of study, or study termination, whichever occurs first. Subjects except those that are deceased, lost to follow-up, or have withdrawn their ICF will enter the long-term follow-up (LTFU) under a separate protocol for at least 15 years.

Inclusion Criteria:

1. ≥ 18 years of age.

2. Documented diagnosed with multiple myeloma according to the IMWG diagnostic criteria.

3. Have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulator-based chemotherapy, and an anti-CD38 therapy (prior exposure can be from different monotherapy or combination regimens), or are refractory to both a proteasome inhibitor and an immunomodulatory agent (i.e., double refractory).

4. Documented disease progression during or within 12 months of the most recent anti-myeloma treatment (except for subjects who received CAR-T as last-line therapy).

5. For subjects with previous BCMA-targeted therapy, the best response should be at least PR, and positive BCMA expression on tumor cells by immunohistochemistry (IHC) or flow cytometry is required before enrollment.

6. The presence of measurable lesion according to IMWG 2016 criteria at screening as determined by any of the following criteria:

   • Serum M-protein level ≥1.0 g/dL or urine M protein level ≥ 200 mg/24 h; or
   • Light chain multiple myeloma without measurable lesions in serum or urine: Involved serum free light chain ≥ 10 mg/dL and abnormal serum κ/λ free light chain ratio.

7. ECOG score of 0 or 1 (refer to Appendix 2)

8. Subjects must have appropriate organ function and meet all the following laboratory test results prior to enrollment:

   • Hematology: Absolute neutrophil count (ANC) ≥ 1×109/L (supportive growth factor is permitted, but must be without supportive treatment within 7 days before the laboratory test); absolute lymphocyte count (ALC) ≥0.3×109/L; platelet count ≥50×109/L (must be without supportive blood transfusion within 7 days before the laboratory test); hemoglobin ≥80 g/L (without transfusion of red blood cells [RBC] within 7 days before the laboratory test; the use of recombinant human erythropoietin is permitted).
   • Liver function: Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5×upper limit of normal (ULN); serum total bilirubin ≤ 1.5×ULN except with known Gilbert's syndrome who have serum bilirubin ≤ 3×ULN.
   • Renal function: Creatinine clearance (CrCl) calculated using the Cockcroft-Gault formula ≥ 40 ml/min.
   • Coagulation function: Fibrinogen ≥1.0 g/L; activated partial thromboplastin time ≤1.5× ULN, prothrombin time (PT) ≤1.5× ULN.
   • Corrected serum calcium ≤11 mg/dL
   • Oxygen saturation (by Fingertip Pulse Oximeter) ≥92%.
   • Left ventricular ejection fraction (LVEF) ≥45%.

9. Female subjects of childbearing potential or male subjects with a partner of childbearing potential agree to use effective contraception methods from screening and continued during study treatment until one year after the last dose.

10. The subject must personally sign an informed consent form approved by the ethics committee in writing.

Exclusion Criteria:

1. Subjects with graft versus host disease (GVHD) or those requiring long-term use of immunosuppressants.

2. Received autologous hematopoietic stem cell transplant (Auto-HSCT) within 12 weeks before apheresis or received prior allogeneic hematopoietic stem cell transplant (Allo-HSCT).

3. Received prior anti-myeloma therapies as follows:

   • Treatment with monoclonal antibodies within 21 days prior to apheresis, or
   • Treatment with cytotoxic chemotherapy or proteasome inhibitor within 14 days prior to apheresis, or
   • Treatment with immunomodulator within 7 days prior to apheresis, or
   • Anti-myeloma therapies other than those described above within 14 days or at least 5 half-lives (whichever is shorter) prior to apheresis.

4. Use of glucocorticoids (defined as prednisone or equivalent > 20 mg/day) at a therapeutic dose within 7 days prior to apheresis. Physiologic replacement, topical, and inhalation steroids are permitted, nevertheless.

5. Severe heart disease: Including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive cardiac failure (New York Heart Association [NYHA] classification grade ≥ III), severe arrhythmia.

6. Unstable systemic diseases judged by the investigator: Including but not limited to severe liver, kidney or metabolic diseases requiring therapy.

7. Malignancies other than multiple myeloma within 5 years prior to screening, excluding adequately treated carcinoma in situ of cervix, basal or squamous epithelial cell skin cancer, localized prostate cancer post radical operation, ductal carcinoma in situ of the breast post radical operation.

8. History of organ transplant.

9. Suspected or confirmed central nervous system involvement.

10. Plasma cell leukemia at the time of screening (>2.0×109/L plasma cells by standard differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary AL amyloidosis.

11. Major surgery within 2 weeks prior to apheresis, or planned surgery within 2 weeks after study treatment administration (subjects who plan to receive surgery under local anesthesia are permitted to be enrolled in this study).

12. Treated with other interventional clinical investigational products within 1 month before signing the informed consent form (ICF).

13. Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection prior to apheresis.

14. Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with detectable hepatitis B virus (HBV) DNA in peripheral blood; positive hepatitis C virus (HCV) antibody with positive HCV RNA in peripheral blood; positive human immunodeficiency virus (HIV) antibody; positive cytomegalovirus (CMV) DNA; positive syphilis test.

15. Pregnant or breastfeeding women or planning to become pregnant while enrolled in this study or within 1 year after receiving study treatment.

16. Stroke, seizure or psychosis within 6 months of signing ICF.

17. Non-hematological toxicities from previous anti-myeloma therapy have not recovered to baseline or grade ≤1 (NCI-CTCAE v5.0, except for alopecia and grade 2 peripheral neuropathy).

18. Any issue that would impair the ability of the subject to receive or tolerate the planned treatment, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.