Safety and Efficacy Study of An Anti-CD38 Antibody Drug Conjugate in Relapsed or Refractory Multiple Myeloma

This is a phase Ib/IIa, open-label, dose-escalation, and extension study to evaluate the safety and efficacy of an anti-CD38 antibody drug conjugate (STI-6129) in patients with relapsed or refractory multiple myeloma.

The study is designed to identify the recommended phase 2 dose (RP2D) of STI-6129 by assessing the safety, preliminary efficacy and pharmacokinetics using a accelerated titration design and a conventional 3+3 study design for dose escalation in stage one and then the second stage will be an expansion study to assess preliminary efficacy.

Inclusion criteria

• Age ≥18 years old, regardless of gender.
• Previously treated with at least three drugs (including PI, IMiD, and anti-CD38 antibody), and relapsed/refractory after the most recent anti-MM therapy.
• Diagnosis of MM according to IMWG criteria with measurable lesions, meeting at least 1 of the following criteria:

• Serum M protein ≥ 0.5g/dL (≥ 5 g/L); or
• Urine M protein ≥ 200mg/24 hours; or
• When the serum free light chain (FLC) ratio is abnormal, the affected FLC level is ≥10mg/dL (≥100 mg/L) (the normal FLC ratio is 0.26 to 1.65).
• ECOG performance status score is 0, 1, or 2.
• Willing and able to comply with the study schedule and all other study protocol requirements.
• Women of childbearing potential (WOCBP) (infertile women are defined as sexually mature females who had undergone a hysterectomy or bilateral oophorectomy or bilateral salpingectomy or bilateral tubal ligation/closure, or who are infertile due to a congenital or acquired condition or spontaneously menopausal for ≥ 12 months) must have a negative blood pregnancy test during the screening. Female subjects of childbearing potential and male subjects with fertility must use a highly effective method of contraception from screening to 6 months after the last treatment.

Exclusion criteria

• Known hypersensitivity to any of the ingredients of this product.
• Diagnosis of active plasma cell leukemia.
• Diagnosis of systemic light chain amyloidosis.
• MM involving the central nervous system.
• Has POEMS syndrome.
• There is spinal cord compression associated with MM.
• Needs to take concomitant drugs with a strong inhibitory effect or a strong induction effect on CYP3A4.
• Had received plasma exchange therapy within 28 days before the first administration of the study drug.
• Had received the following anti-tumor treatments before the first administration of the study drug: monoclonal antibody or cytotoxic drug or radiotherapy within 28 days; immunoregulator, targeted therapy or epigenetic therapy or investigational medical product or invasive investigational medical device or other anti-myeloma therapy within 28 days or 5 half-lives (whichever is shorter); proteasome inhibitor or anti-tumor traditional Chinese medicine treatment or corticosteroids with a cumulative dose of more than 140 mg prednisone (or equivalent) or a single dose of more than 40 mg/day dexamethasone (or equivalent) within 14 days.
• Had received CAR-T therapy or allogeneic hematopoietic stem cell transplantation therapy within 6 months before the first administration of the study drug, or have a concomitant disease of active graft-versus-host disease (GvHD) at screening.
• Had received autologous hematopoietic stem cell transplantation within 12 weeks before the first administration of the study drug.
• Had undergone major surgery or eye surgery within 28 days before the first administration of the study drug.
• Other malignant diseases within 3 years before the first administration of the study drug.
• History of grade ≥3 (muscle paralysis, eyelid disease, glaucoma requiring drug control, tearing eyes), or grade ≥2 any other ocular disease (as judged by NCI-CTCAE version 5.0) at screening.
• Has ≥ Grade 3 neuropathy or Grade 2 neuropathy with associated pain.
• The toxicity caused by the previous anti-tumor treatment did not subside to ≤ grade 1.
• Has the following hematological test results within 7 days before the first administration of the study drug:

• Hemoglobin <80g/L
• Platelet count <50×10^9/L
• Absolute neutrophil count <1.0×10^9/L
• Has the following blood chemistry test results within 7 days before the first administration of the study drug:

• Estimated creatinine clearance <30mL/min.
• AST or ALT>3×upper limit of normal (ULN) or serum total bilirubin> 1.5×ULN.
• Severe or uncontrolled cardiovascular and cerebrovascular diseases requiring treatment, including:

• New York Heart Association class>2;
• Unstable angina pectoris that cannot be controlled by drugs;
• Myocardial infarction occurred within 6 months before the first administration of the study drug;
• Poorly controlled arrhythmias;
• 12-lead ECG QTcF>470msec;
• Left ventricular ejection fraction <40%;
• Poorly controlled hypertension ;
• Stroke, cerebrovascular accident, or transient ischemic attack occurred within 6 months before the first administration of the study drug.
• Meets any of the following criteria:

• Known chronic obstructive pulmonary disease (COPD) and forced expiratory volume in 1 second (FEV1) <50% of predicted normal;
• Known moderate or severe persistent asthma, or a history of asthma within the past 2 years, or current uncontrolled asthma of any classification;
• with interstitial lung disease requiring corticosteroid therapy, drug-induced interstitial lung disease, a history of radiation pneumonitis, orclinically active interstitial lung disease suggested by any current evidence before the first administration of the study drug.
• Has an active bacterial, viral, or fungal infection or needs for intravenous antibiotic administration (IV) within 72 hours before the first administration of the study drug.
• Active or uncontrolled HBV , HCV , HIV positive.
• Is currently pregnant or breast feeding.
• Has any active severe mental illness, medical illness, or other symptoms/conditions that may affect treatment, compliance, or the ability to provide informed consent, as determined by the investigator.