Study of YK012 in B-cell Acute Lymphoblastic Leukemia

The purpose of this study is to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of YK012 administered as monotherapy in participants with B-cell acute lymphoblastic leukemia (B-ALL).

YK012 is a bispecific antibody designed to link B cells and T cells resulting in T-cell activation and a cytotoxic T-cell response against cluster of differentiation (CD)19 expressing cells. Relapsed/refractory B-ALL in adult patients is an aggressive malignant disease with dismal prognosis. This study is designed in 2 parts as described below: Phase Ib (dose escalation) and Phase II (dose expansion). If in Phase Ib it is observed in adult subjects at doses with manageable risk and antitumor activity, studies in pediatric subjects can be initiated to explore safety and efficacy in pediatric subjects, as well as pharmacokinetic profiles.

Eligibility Criteria:
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. Eastern Cooperative Oncology Group Performance Status (ECOG) of 0-2.
3. An estimated survival time of more than 12 weeks.
4. A definitive diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with any of the following conditions:

   1. Ph-negative B-ALL with any of the following: i. Failure to achieve complete remission after initial induction therapy. ii. Failure to achieve complete remission after salvage treatment. iii. Relapse with first remission duration ≤12 months. iv. Second or later relapse. v. Relapse after hematopoietic stem cell transplantation (HSCT).
   2. Ph-positive B-ALL: failure to 1 or more tyrosine kinase inhibitors (TKIs), or intolerance to treatment with TKIs, or with the T315I mutation.
5. ≥ 5% blasts in the bone marrow by morphologic assessment.
6. 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.
7. Adequate hematological and organ function.
8. 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.
9. 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. Burkitt´s Leukemia according to World Health Organization (WHO) classification.
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 3 weeks
   3. Radiotherapy or chemotherapy (except for intrathecal chemotherapy and dexamethasone), or treatment with Chinese traditional/patent medicine that has definite antitumor effect within 2 weeks
   4. Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter
   5. Receipt of any live attenuated vaccines or live virus vaccine within 4 weeks
   6. Autologous stem cell transplantation within 6 weeks
   7. History of organ transplant, or allogeneic stem cell transplantation within 12 weeks.
3. Any active acute graft-versus-host disease (GvHD), grade 2-4 (according to Glucksberg criteria) or active chronic GvHD requiring systemic treatment.
4. Other malignancy within 5 years, except 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 meningeal involvement with clinical signs, 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 (e.g., myocardial infarction, unstable angina)
   2. Coronary angioplasty or stenting within 6 months prior to enrollment
   3. Clinically significant unstable arrhythmias (e.g., atrial fibrillation), however, atrial fibrillation has been controlled for over 30 days prior to the first dose of YK012 were allowed
   4. New York Heart Association (NYHA) stage III or higher congestive heart failure
   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, mean of triplicate measurements) ≥ 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. History of CD19 targeted therapy and positive test result for immunogenicity of YK012 at screening.
10. Any major organ surgery or significant trauma within 4 weeks prior to the first dose of YK012, or those requiring elective surgeries during the study, and all AEs associated with surgery or significant trauma have not recovered to Grade ≤1 or baseline graded by CTCAE v5.0 before the first dose of the YK012.
11. 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 immunosuppressive therapy within 4 weeks prior to study entry.
12. 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)\>ULN of the testing agency; Hepatitis C antibody (HCV-Ab) positive and hepatitis C virus-RNA (HCV-RNA)\>ULN of the testing agency; Anti-human immunodeficiency virus (Anti-HIV) positive. Participants will be excluded from the study if any of the above criteria is met.
13. Uncontrolled active infections requiring oral or intravenous systemic therapy, except for local treatment.
14. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once a month or more frequently).
15. Pregnant or lactating women.
16. Known mental disorder that may affect study compliance or poor compliance.
17. Other serious systemic diseases or laboratory abnormalities or other reasons that the investigator believes are not appropriate for participating in the study.