A Study of YKST02 in Participants With Relapsed or Refractory Multiple Myeloma

A Multicenter, Open-label, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Efficacy of YKST02 in Participants With Relapsed or Refractory Multiple Myeloma

This study aims to provide a basis for further clinical development of YKST02. YKST02 is a study medicine that targets multiple myeloma and activates the human body to fight against this disease.

This study is the first-in-human clinical trial to evaluate the safety, tolerability, pharmacokinetic (PK) profile and preliminary efficacy of YKST02 in patients with relapsed or refractory multiple myeloma (MM). Multiple Myeloma (MM) is a cancer of the blood's plasma cells (blood cell). YKST02 is a bispecific antibody bridging CD3-expressing T cells and BCMA-expressing multiple myeloma cells to induce T cells-mediated cytotoxicity. This study consists of dose escalation phase and dose expansion phase.

Inclusion Criteria:

1. Participants or their legally acceptable representative must sign an ICF indicating that the participants understand the purpose of, and procedures required for the study and are willing to participate in the study.

2. Diagnosis of multiple myeloma according to the IMWG criteria.

3. Receipt of at least two prior classes of drugs either in separate regimens or as combinations. The three classes are defined as: An immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 drug.

4. Measurable disease at screening, as defined by at least 1 of the following:

   1. Serum M-protein ≥0.5 g/dL;
   2. Urinary M-protein excretion ≥200 mg/24 hours;
   3. Abnormal serum free light chain (FLC) ratio ( <0.26 or >1.65) and serum immunoglobulin FLC≥10 mg/dL.

5. Eastern Cooperative Oncology Group Performance Status (ECOG) of 0-1.

6. An estimated survival time of more than 12 weeks.

7. Recovery to Grade 0-1 (Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0) from adverse events related to prior therapy except alopecia.

8. Adequate hematological and organ function.

9. Female participants of childbearing potential must have a negative serum pregnancy test at screening. Female patients who are sexually active must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.

10. Male participants must agree to use reliable methods of contraception (barrier methods or sexual abstinence) and avoid sperm donation throughout the study period and until 3 months after the last dose.

Exclusion Criteria:

1. Plasma cell leukemia (>2.0×10^9/L plasma cells by standard differential), Waldenstrom's Macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary light-chain amyloidosis.

2. History of antitumor therapy as follows, before the first dose of study drug:

   1. Targeted therapy with small molecule drug within 2 weeks or 5 half-lives, whichever is longer;
   2. Targeted therapy with macromolecular drug or Immunomodulatory agent therapy within 2 weeks;
   3. Chemotherapy within 2 weeks;
   4. Treatment with an investigational drug within 2 weeks or 5 half-lives, whichever is shorter;
   5. Radical/extensive radiotherapy within 4 weeks, or local palliative radiotherapy within 2 weeks, or acute toxicity induced by previous radiotherapy have not recovered to grade ≤1;
   6. Autologous stem cell transplantation within 12 weeks;
   7. History of organ transplant, or allogeneic stem cell transplantation within 6 months;
   8. Prior treatment with any B cell maturation antigen (BCMA) targeted therapy;
   9. Prior treatment with any BCMA targeted chimeric antigen receptor modified [CAR]-T cells therapy.

3. Any active acute graft-versus-host disease (GvHD), grade 2-4 (according to Glucksberg criteria) or active chronic GvHD requiring systemic treatment within 2 weeks.

4. Prior myelodysplastic syndrome or malignancy within 5 years, except for localized malignancies that have been adequately treated or free of the disease for ≥ 5 years, e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-muscle invasive bladder cancer, localized prostate cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast.

5. Active central nervous system (CNS) involvement or exhibition of clinical signs of meningeal involvement of multiple myeloma, or other evidence of uncontrolled metastases to the CNS or meninges, judged by the investigator.

6. (a) History of or current relevant CNS pathology as epilepsy, seizure, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis; (b) Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI.

7. History or evidence of cardiovascular disease, including:

   1. Acute coronary syndromes (eg, myocardial infarction, unstable angina) within 6 months prior to enrollment;
   2. Coronary angioplasty or stenting within 6 months prior to enrollment;
   3. Clinically significant unstable arrhythmias (eg, atrial fibrillation), however, atrial fibrillation has been controlled for over 30 days prior to the first dose of YKST02 were allowed;
   4. New York Heart Association (NYHA) stage III or higher congestive heart failure within 6 months prior to enrollment; Cardiac valve morphological abnormalities recorded by ECHO (≥ grade 2), note that grade 1 cardiac valve morphological abnormalities (such as mild regurgitation/stenosis) were allowed, but participants with moderate valve thickening were excluded;
   5. Left ventricular ejection fraction (LVEF) below lower limit of the study center, or LVEF<50% if there is no lower limit at the study center;
   6. The Fridericia-corrected QT interval (QTcF) ≥ 470 msec (female) or ≥ 450 msec (male)；
   7. Implantable defibrillator;
   8. Clinically uncontrollable hypertension (i.e., SBP≥160 mm Hg and/or DBP≥100 mm Hg).

8. Known allergy to monoclonal antibody drugs or exogenous immunoglobulin.

9. Any major organ surgery or significant trauma within 4 weeks prior to the first dose of YKST02, or those requiring elective surgeries during the study, and all AEs associated with surgery or significant trauma have not recovered before the first dose of the YKST02.

10. Regular dose of systemic corticosteroids during 4 weeks prior to initiation of study drug, or anticipated need of corticosteroids exceeding prednisone 20 mg/day or equivalent during the trial, or any other systemic immunosuppressive therapy within 4 weeks prior to study entry.

11. Virological tests: Hepatitis B virus surface antigen (HBsAg) positive and/or hepatitis B core antibody (HBcAb) positive, and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) quantitative >ULN of the testing institution; Hepatitis C antibody (HCV-Ab) positive and hepatitis C virus-RNA (HCV-RNA) quantitative > ULN of the testing institution; Anti-human immunodeficiency virus (Anti-HIV) positive. Participants will be excluded from the study if any of the above criteria is met.

12. Uncontrolled active infections requiring oral or intravenous systemic therapy, except for local treatment.

13. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once a month or more frequently).

14. Pregnant or lactating women.

15. Known mental disorder that may affect study compliance or poor compliance.

16. Receipt of any live attenuated vaccines or live virus vaccine within 4 weeks prior to the first dose of study treatment.

17. Other serious systemic diseases or laboratory abnormalities or other reasons that the investigator believes are not appropriate for participating the study.