Evaluate CART-BCMA in Patients With Relapsed and/or Refractory Multiple Myeloma

A Phase I Clinical Trial to Evaluate CART-BCMA in Patients With Relapsed and/or Refractory Multiple Myeloma

This is a Phase 1, multicenter, open-label study o evaluate the safety and efficacy of CART-BCMA in subjects with relapsed/refractory multiple myeloma.

The study will consist of 2 parts: dose-escalation (Part A) and dose-expansion (Part B). The dose-escalation part (Part A) of the study is to evaluate the safety and tolerability of increasing dose levels of CART-BCMA to establish a recommended dose (RD); and the dose-expansion part (Part B) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of CART-BCMA at the RD.

Inclusion Criteria:

• At least 18 years old (inclusive), gender is not limited;
• Multiple myeloma patients who have received at least 3-line previous multiple myeloma therapy and have failed at least through proteasome inhibitors and immunomodulators; Each line of treatment has at least 1 complete treatment cycle, unless the best remission for the treatment is recorded as disease progression (PD) (according to the IMWG Efficacy Evaluation Criterialpublished in 2016, Appendix 4); PD must be recorded during or within 12 months after the last treatment;
• Bone marrow specimens were confirmed by immunohistochemistry or flow cytometry as positive BCMA expression in plasma cells and myeloma cells (>5%);
• The presence of measurable lesions during screening was defined as any of the following:

Serum M protein ≥1 g/dL (≥10 g/L); Urinary M protein level ≥200 mg/24 h; Serum light chain (FLC) : abnormal serum FLC ratio (< 0.26 or > 1.65), and affected FLC≥10 mg/dL (100mg/L);

• ECOG score (Appendix 1) 0~1;
• Expected survival time ≥3 months;
• The mononuclear cells meet the following standards within 3 days before collection:

Hematology:≥0.5×109/L[The use of past granulocyte colony stimulating factor (G-CSF) is allowed, but patients shall not receive this supportive treatment within 7 days prior to the screening phase of laboratory examination];≥1.0 ×109 /L[Ex-granulocyte colony-stimulating factor (G-CSF) is allowed, but subjects shall not receive this supportive treatment within 7 days prior to the screening laboratory examination];Subjects' platelet count ≥50×109/L (Subjects shall not receive blood transfusion support within 7 days before the screening laboratory examination);≥8.0 g/dL (Recombinant Human Erythropoietin is allowed) [Subjects have not received a red blood cell infusion (RBC) within 7 days prior to the screening phase laboratory examination]; Heart:Left ventricular ejection fraction (LVEF) ≥ 50%; Lung:Blood oxygen saturation ≥91% under non-inhaled oxygen condition; Kidney:Creatinine clearance (CRCL) or glomerular filtration rate (GFR) (Cockcroft-Gault formula) ≥30 mL/min; Liver:Total bilirubin (serum) ≤1.5 × ULN;Gilbert's disease patients with >1.5 × ULN could be enrolled with the consent of the Sponsor; Blood coagulation:Plasma prothrombin time (PT) ≤1.5 × ULN, international standardized ratio (INR) ≤1.5 × ULN, partial prothrombin time (APTT) ≤1.5 × ULN;

• Peripheral venous access can meet the needs of single collection and intravenous drip;
• The subject agrees to use reliable contraceptive methods for contraception within 1 year after signing the informed consent form to the infusion. Including but not limited to: abstinence, men undergoing vasectomy, implantable progesterone contraceptives that can inhibit ovulation; intrauterine contraceptive devices; hormone-releasing intrauterine devices; sexual partner sterilization methods; copper intrauterine devices, Correct use of proven compound hormonal contraceptives that can inhibit ovulation; progesterone contraceptives that can inhibit ovulation. At the same time, female subjects should promise not to donate eggs (egg cells, oocytes) for assisted reproduction within 1 year after the infusion;
• Volunteer to participate in clinical trials and sign Informed Consent Form;

Exclusion Criteria:

• Subjects who are known to have allergic reactions, hypersensitivity, intolerance, or contraindications to any component of CART-BCMA or any drugs that may be used in the study (including fludarabine, cyclophosphaamide, or tozumab), or who are allergic to β-lactam antibiotics, or who have had severe allergic reactions in the past;
• Prior to any CAR-T therapy or BCMA-targeted therapy;
• Have received the following anti-MM treatment within the prescribed time range before single calyzer:

Has received small molecule targeted therapy within 4 weeks or 5 half-lives, whichever is longer; treatment with a large molecule within 4 weeks or 2 half-lives, whichever is longer; received cytotoxic therapy, proteasome inhibitor, or modern Chinese medicine preparation with anti-tumor effect within 2 weeks; received immunomodulatory drug therapy within 1 week; received radiotherapy within 1 week

• Participated in a clinical trial within 4 weeks before the single collection;
• Patients who received autologous hematopoietic stem cell transplantation (ASCT) or previous allogeneic stem cell transplantation within 12 weeks before a single collection (no time limit);
• People who received live vaccine or attenuated vaccine within 4 weeks before the CART-BCMA harvest; Note: Inactivated viral vaccines for seasonal influenza are allowed for injection; Intranasally administered live attenuated influenza vaccines are not allowed;
• Received any of the following treatments within 7 days prior to the single collection or as determined by the investigator to require long-term treatment during the study period:

Systemic steroid therapy (except inhalation or topical use), Immunosuppressive therapy, Graft versus host therapy, Preventive treatment of central nervous system

• Incomplete recovery or stabilization to grade 1 (NCI-CTCAE v5.0) of toxicity (including peripheral neuropathy) caused by previous treatment;
• MM is suspected to be involved in the central nervous system or meninges and confirmed by MRI or CT, or to have other active central nervous system diseases;
• Patients with plasma cell leukemia or Waldenstrom macroglobulinemia or POEMS syndrome (polyneuropathy, organ enlargement, endocrine disorder, monoclonal protein, and cutaneous disease) or amyloidosis at the time of screening;
• Heart disease: Existing heart failure (NYHA classification ≥II, Appendix 2), unstable angina pectoris, or severe heart disease as determined by the investigator; Myocardial infarction had occurred no more than 6 months before single arthroplasty. Had an episode of unstable angina pectoris, severe arrhythmia as determined by the researchers, or had undergone coronary artery bypass grafting (CABG) no more than 3 months before the single harvest;
• Poor control of hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg) or with hypertensive crisis or hypertensive encephalopathy;
• Patients who had undergone major surgery or plasma separation other than diagnosis or biopsy within 4 weeks prior to the study alone, or who were expected to undergo major surgery during the study period; Note: Patients who plan to undergo surgery under local anesthesia may participate in the study. Kyphoplasty or vertebra osteoplasty are not considered major surgery;
• Receiving thrombolytic, anticoagulant or antiplatelet therapy;
• Infections require intravenous antibiotics or hospitalization;
• Patients with active hepatitis B; Hepatitis C virus (HCV) antibody positive; HIV-positive persons; Syphilis primary screening antibody positive; A) Inactive/asymptomatic patients with carryable, chronic, or active HBV who meet the following criteria are eligible for inclusion: HBV DNA <500 IU/mL (or 2500 copies /mL) at the time of screening.
• Women who are pregnant or lactating;
• The investigator considers that the subject is unsuitable to participate in this clinical study due to any abnormal clinical or laboratory examination or other reasons.