Anti BCMA CAR- T Cell Therapy for Adults With Relapsed or Refractory Multiple Myeloma

Phase I/II Open-label Study Evaluating The Safety And Efficacy of Anti BCMA CAR-T Cell Therapy in Adults With R/ R Multiple Myeloma

The mail purpose of this study is to estimate the safety and the efficacy of anti-BCMA CAR- T cell immunotherapy for adults with relapsed or refractory multiple myeloma

Locally manufactured second generation autologous humanized anti-BCMA cells are used for immunotherapy. Protocol treatment includes leukapheresis in order to harvest T cells, lymphodepleting conditioning (fludarabine 30 mg/m2+ cyclophosphamide 300 mg/2(days -5-3)) followed by one anti (day 0) BCMA CAR-T cell infusion.

The Main research objectives of the Phase I:

To preliminarily explore the safety (incidence of CRS, ICANS, HLH, infections, late ICAHT, p arkinsonism and cytopenias) and tolerability.

The Secondary research objectives of the Phase I:

To explore the pharmacokinetics of CAR-T cells.

The Main research objectives of the Phase II:

Overall response rate, including partial response (PR), very good partial response (VGPR), complete response (CR) and stringent complete response(sCR) rates.

The Secondary research objectives of the Phase II:

Duration of response (DOR). Progression-free survival rates. Overall survival rates.

Inclusion Criteria:

1. Male or female, aged ≥18 years.

2. Willing and able to give written, informed consent.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.

4. Relapsed or refractory multiple myeloma according to IMWG criteria with two previous lines of therapy and resistance to proteosome inhibitors and immunomodulators.

5. Adequate organ system function including

   - Creatinine clearance ≥30 cc/min.

   - Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x upper limit of normal (ULN).

   - Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome.

   - Left ventricular ejection fraction (LVEF) ≥50% (by echocardiogram [ECHO] or

   - Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea.

6. Have no active GVHD (Grade 2-4)

7. Adequate bone marrow (BM) function

   • Absolute neutrophil count ≥1.0 × 10^9/L.
   • Absolute lymphocyte count ≥0.3 × 10^9/L (at enrolment and prior to leukapheresis).
   • Haemoglobin ≥80 g/L.
   • Platelets ≥50 × 10^9/L

Exclusion Criteria:

1. Females who are pregnant or lactating.
2. History or presence of clinically relevant CNS pathology such as epilepsy, paresis, aphasia, stroke within prior 3 months, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis.
3. Patients with active CNS involvement by malignancy. Patients with history of central nervous system (CNS) involvement with malignancy may be eligible if CNS disease has been effectively treated and provided treatment was at least 4 weeks prior to enrolment (at least 8 weeks prior to CAR-T infusion).
4. Clinically significant, uncontrolled heart disease or a recent (within 12 months) cardiac event.
5. Active bacterial, viral or fungal infection requiring systemic treatment. Active or latent hepatitis B infection or hepatitis C infection. Testing positive for human immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis.
6. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months.

6. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia, or idiopathic pneumonitis.

7. History of other malignant neoplasms unless disease free for at least 24 months (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal therapy allowed).

8. The following medications are excluded:

• Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 72 hours prior to CAR-T administration. However, physiological replacement, topical, and inhaled steroids are permitted.
• Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis or CAR-T cells infusion.
• Cytotoxic chemotherapies within 1 week of CAR-T cellsinfusion and 1 week prior to leukapheresis.
• Granulocyte-colony stimulating factor less than 14 days prior to leukapheresis.
• Live vaccine ≤4 weeks prior to enrolment.
• Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning chemotherapy.

Prior limited radiation therapy within 2 weeks of CAR-T cells infusion. 9. Prior anti BCMA therapy 10. Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine or tocilizumab.

11. Any other condition that in the Investigator's opinion would make the patient unsuitable for the clinical trial.