A Phase I Clinical Trial of Y150 in the Treatment of Relapsed or Refractory Multiple Myeloma

This is a Phase I, open-label，dose-escalation trial in patients with relapsed or refractory multiple myeloma. There are two parts of the study: a dose-escalation part and a dose-expansion part. Dose escalation follows an accelerated design initially with 2 single subject cohorts (Cohorts 1-2) and switches to a classical 3+3 design (Cohorts 3-7). Dose-expansion means that at least 9 subjects (included subjects of the dose-escalation part) will be selected in 1 - 3 dose levels to focus on the pharmacokinetics (PK) / pharmacodynamic (PD) features and recommended dose for Phase II (RP2D). Additional purpose of the study is to find out whether the study drug has anti-tumor effects.

Inclusion criteria

• Male or female ≥ 18 years.
• Subject has a history of multiple myeloma with relapsed and refractory disease, and must have received at least 2 prior multiple myeloma treatment regimens (including a proteasome inhibitor and an immunomodulatory agent), or can not tolerate the toxicity of PIs and IMIDS; or have drug resistance to one and toxic intolerance to the other.

• Relapsed multiple myeloma is defined as IMWG criteria in 2016, including clinical relapse or relapse after CR.
• Refractory multiple myeloma is defined as failure of initial or salvage therapy to achieve at least a minimal response (only achieve SD after treatment ≥ 2 cycles ), or disease progression during treatment or within 60 days after the last treatment.
• Subjects must have measurable disease, including at least one of the criteria below:

• M-protein ≥ 10 g/L by SPEP/immunofixation for subjects with immunoglobulin class G (IgG) myeloma , M-protein ≥ 5g/L for subjects with IgA, IgD, IgE, IgM myeloma or
• ≥ 200 mg/24 hours urine collection by UPEP or
• Serum free light chain (FLC) levels ≥ 100 mg/L and an abnormal kappa/lambda (κ/λ) ratio in patients without detectable serum or urine M-protein
• The interval between the last anti-tumor treatment and the first administration of Y150 (including PIS and IMADs) ≥4 weeks, the interval between CD38 mAb administration and the first administration of Y150 ≥12 weeks;
• ECOG performance status 0 - 2;
• Life expectancy ≥ 3 months
• Adequate hematological function as evidenced by meeting all the following requirements:

• Absolute neutrophil count ≥1.0×109/L (growth factor support not allowed within 48h)
• Hemoglobin > 70 g/L( without blood transfusion within 7 days)
• Platelet count ≥50×109/L(without transfusion within 7 days)
• Adequate hepatic function as evidenced by meeting all the following requirements:

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST), and alanine aminotransferase (ALT)≤ 2.5 × ULN;
• Calculated creatinine clearance (CrCL) ≥ 30 mL/min
• Understand and voluntarily sign written informed consent.

Exclusion criteria

• Subject has central nervous system involvement of multiple myeloma.
• Subject has received ≥ 10 mg/day prednisone equivalent within one week before starting Y150.
• Subject with primary or secondary plasma cell leukemia.
• Subject had a prior autologous stem cell transplant ≤ 12 weeks months prior to starting Y150, or had a prior autologous stem cell transplant history.
• Subject received a chimeric antigen receptor T (CAR T) cell product ≤ 6 months prior to starting Y150.
• Concurrent malignancy within 5 years prior to entry other than adequately treated cervical carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma, prostate cancer under active surveillance, prostate cancer that has undergone definitive treatment, ductal carcinoma in situ of the breast, or ≤ T1 urothelial carcinoma.
• Allergy to Abs drugs or human protein.
• Active infection(CTCAE Grade ≥2).
• Subjects with severe respiratory disease, and to be unsuitable to participate in study by investigators judgment.
• Severe cardiovascular disease, including a history of CABG or PCI, myocardial infarction within 6 months of study entry, unstable angina ,NYHA class III or IV heart failure, uncontrolled hypertension or left ventricular ejection fraction <50%
• QTc interval > 480 ms; Family or personal with a history of long or short QT syndrome; significant clinical history of ventricular arrhythmias, or currently receiving antiarrhythmic drugs or implanted defibrillator to treat ventricular arrhythmias.
• Patients with a history of active autoimmune diseases (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis etc.), except when the disease is in a stable state (without systemic immunosuppressant treatment, the symptoms are stable for more than 6 months).
• Patients with severe hyperthyroidism or hypothyroidism.
• Patients with metabolic diseases such as uncontrolled diabetes, severe gastrointestinal bleeding, severe diarrhea (Grade ≥ 2 according to CTCAE), or severe gastrointestinal obstruction requiring intervention.
• Patients with a history of immunodeficiency, including HIV positive.
• HIV antibody, TP antibody and HCV antibody were positive, HBsAg positive and hepatitis B virus DNA test showed that patients with active hepatitis B (HBV-DNA ≥ 1000cps/ml).
• Patients who have received inoculation of (attenuated) live virus vaccine within 4 weeks before the first administration.
• Pregnant, lactating women, or females or males who have fertility plan within 6 months during the study and after the end of the medication.
• Patients with a previous history of definite neurological or psychiatric disorders, and investigator believe that it affects patients' cognitive function or compliance, including unstable epilepsy, dementia, schizophrenia, etc.
• Any condition that the investigator believes may not be appropriate for participating the study.