Overview

An effective treatment for adults and children B-ALL represents a significant unmet need. CN201 has demonstrated efficacy in nonclinical models of leukemia .CN201 has a longer half-life, thus long term continuous intravenous infusion is not necessary for clinical use. The present study will be conducted in 2 parts: Phase Ib is a dose finding phase to identify the RP2D. Phase II will allow further evaluation of the safety and efficacy of CN201 at the RP2D.

Eligibility

Adult cohort:

Inclusion criteria:

        Subjects are eligible to be included in the study only if all the following criteria are
        met.
          1. Subjects aged ≥18 years old on the day of signing the informed consent form.
          2. Subjects with B-ALL who have more than 5% blasts (primitive/naive) in the bone marrow
             will be enrolled according to the following criteria:
             a) Subjects with 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 allogeneic HSCT b) Subjects with
             Ph-positive B-ALL who have received 2 (or more) tyrosine kinase inhibitors (TKIs) and
             meet the refractory/relapse criteria above or, those with the T315I mutation.
          3. Subjects with ECOG performance score of 0 to 2.
          4. At least 3 months expected survival.
          5. Adequate organ function, further defined as:
               -  Liver Function Total bilirubin ≤1.5 × upper limit of normal (ULN) (Patients with
                  evidence based Gilbert's Syndrome, ≤ 3×ULN) Alanine aminotransferase (ALT)≤3 ×
                  ULN Aspartate aminotransferase (AST)≤3 × ULN
               -  Renal Function Serum/plasma creatinine, or Creatinine clearance ≤1.5 × ULN, or
                  ≥50 mL/min (calculated by Cockcroft-Gault formula)
               -  Cardiopulmonary Function Echocardiography: Left ventricular ejection fraction
                  (LVEF) ≥ 50% without clinically significant pericardial effusion; 12-lead
                  electrocardiogram (ECG) results: No clinically significant ECG abnormalities
                  [atrial fibrillation of any grade, degree II AV block or degree III AV block, or
                  QTcF > 470 msec (female) or > 450 msec (male); other uncontrolled symptomatic
                  arrhythmia]).
             Blood oxygen saturation > 92% (non-oxygenated)
          6. Female subjects must be non-pregnant and non-lactating and agree to remain abstinent
             (avoid heterosexual intercourse) or must use an acceptable, highly effective double
             contraception method from Screening until 90 (±7 days) days after the last dose of the
             CN201. During this period, women are not allowed to donate eggs. Double contraception
             is defined as a condom AND 1 other from the following:
               1. Established hormonal contraception (with approved oral contraceptive pills,
                  long-acting implantable hormones, injectable hormones).
               2. A vaginal ring or an intrauterine device (IUD).
               3. Documented evidence of surgical sterilization at least 6 months prior to
                  screening (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or
                  bilateral oophorectomy for women or vasectomy for men [with appropriate
                  post-vasectomy documentation of the absence of sperm in semen] provided the male
                  partner is a sole partner).
               4. Women without childbearing potential must be post menopausal for ≥12 months.
                  Post-menopausal status will be confirmed through testing of follicle-stimulating
                  hormone (FSH) levels ≥40 IU/L at Screening for amenorrhoeic female subjects.
                  Females who are abstinent from heterosexual intercourse will also be eligible.
               5. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation
                  methods) and withdrawal are not considered highly effective methods of birth
                  control. Subject complete abstinence for the duration of the study and for 90
                  days after the last study treatment is acceptable.
               6. Female subjects who are in same-sex relationships are not required to use
                  contraception.
             Male subjects must be agree to remain abstinent (avoid heterosexual intercourse) or
             willing to use a highly effective method of contraception throughout the study period
             and for 90 days after the last dose of CN201 and agree to avoid sperm donation.
          7. Subjects must be able to understand and sign the paper informed consent form before
             any study-specific procedure is conducted.
        Exclusion criteria:
        Subjects will be excluded from the study if any of the following criteria is met.
          1. Subjects with Burkitt's leukemia.
          2. Subjects who have received bbbanti-CD19 therapy within 3 months prior to the first
             dose of CN201.
          3. Subjects who have received allogeneic HSCT within 12 weeks prior to the first dose of
             CN201.
          4. Subjects who have received autologous HSCT within 6 weeks prior to the first dose of
             CN201.
          5. Subjects who have received radiotherapy or chemotherapy within 2 weeks, prior to the
             first dose of CN201 (except for intrathecal chemotherapy and dexamethasone) or within
             5 half-lives of small molecule targeted drugs.
          6. Subjects who have received immunotherapy within 3 weeks prior to the first dose of
             CN201.
          7. Subjects who have received other investigational agents (not yet approved by any
             regulatory agency) within 3 weeks prior to the first dose of CN201.
          8. Subjects who have received prior treatment with CAR-T within 3 months prior to the
             first dose of CN201.
          9. Subjects with major organ surgery (excluding puncture biopsy) or significant trauma
             within 4 weeks prior to the first dose of CN201, or elective surgery during the study.
         10. Subjects who use of live attenuated vaccine within 4 weeks prior to the first dose of
             CN201
               1. Exception: Use of an approved coronavirus disease 2019 (COVID-19) vaccine is
                  allowed, but the last dose of COVID-19 vaccine must be administered at least 2
                  weeks prior to the first dose of CN201.
               2. For active subjects enrolled in this study, COVID-19 vaccination is allowed after
                  8 weeks treatment have been completed and the safety data are abailable.
         11. Subjects who had adverse reactions prior to anti-tumor therapy that have not recovered
             to Grade ≤1 assessed by NCI-CTCAE Version 5.0 (except for toxicities such as alopecia
             judged by the Investigator as no safety risk).
         12. History or presence of clinically relevant CNS pathology such as epilepsy,
             hemorrhagic/ischemic stroke, severe brain injuries, dementia, Parkinson's disease,
             cerebellar disease, organic brain syndrome, or psychosis.
         13. Subjects with clinically symptomatic metastases to the central nervous system or
             meninges, or other evidence of uncontrolled metastases to the CNS or meninges, judged
             by the Investigator. History CNS leukemia that is controlled with intrathecal therapy
             is allowed.
         14. Have a serious uncontrolled active infection.
         15. Subjects with a history of immunodeficiency, including history of any positive test
             result for human immunodeficiency virus (HIV) antibody.
         16. Subjects with chronic infection with hepatitis B, defined as having a positive
             hepatitis B surface antigen (HBsAg) test and/or detectable level of hepatitis B virus
             DNA at Screening, or hepatitis C infection, defined as having a positive hepatitis C
             virus (HCV) antibody test.
         17. Subjects with current or previous interstitial lung disease.
         18. Subjects with concomitant secondary malignancies (except adequately treated
             non-melanomatous skin cancers, ductal carcinoma in situ, superficial bladder cancer,
             prostate cancer, or in situ cervical cancers) are excluded unless a complete remission
             is achieved at least 5 years prior to study entry and no additional therapy is
             required or anticipated to be required during the study period.
         19. Subjects with a history of serious cardiovascular and cerebrovascular diseases,
             including but not limited to:
               1. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia
                  requiring clinical intervention, degree II-III atrioventricular block, or QTcF >
                  470 msec (female) or > 450 msec (male).
               2. Acute coronary syndrome, congestive heart failure, stroke, or other Grade 3 or
                  higher cardiovascular and cerebrovascular events within 6 months prior to the
                  first dose of CN201.
               3. New York Heart Association (NYHA) functional class ≥II or left ventricular
                  ejection fraction (LVEF) <50%.
         20. Subjects with uncontrollable space effusion (e.g. pleural effusion, abdominal
             effusion, pelvic effusion, etc.), as judged by the Investigator.
         21. Subjects with active autoimmune diseases that may relapse (e.g., systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid
             disease, vasculitis, psoriasis, etc.) or history of autoimmune disease with potential
             CNS involvement.
         22. Any active acute Graft-versus-Host Disease (GvHD), Grade 2-4 according to the
             Glucksberg criteria or active chronic GvHD requiring systemic treatment.
         23. Any systemic therapy against GvHD within 2 weeks before start of CN201.
         24. Subjects who previously received immunotherapy and experienced Grade ≥3 immune-related
             AEs (irAEs).
         25. Subjects with known alcohol or drug dependence.
         26. Subjects with mental disorders or other conditions that pose high noncompliance risks.
         27. Subjects with any other condition or circumstance that would, in the discretion of the
             Investigator, make the subject unsuitable for participation in this clinical study.
        Children cohort
        Inclusion criteria:
        Subjects are eligible to be included in the study only if all the following criteria are
        met.
          1. Subjects aged <18 years old on the day of signing the informed consent form.
          2. Subjects with B-ALL who have more than 5% blasts (primitive/naive) in the bone marrow
             will be enrolled according to the following criteria:
             a) Subjects with 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 allogeneic HSCT b) Subjects with
             Ph-positive B-ALL who have received 2 (or more) tyrosine kinase inhibitors (TKIs) and
             meet the refractory/relapse criteria above or, those with the T315I mutation.
          3. Organ function is generally normal, including liver and kidney function appropriate to
             their age:
             Liver function:
             Total bilirubin: ≤1.5 × (age-appropriate) upper limit of normal (ULN) ALT ≤2.5 ×
             (age-appropriate) ULN AST ≤2.5 × (age-appropriate) ULN Serum/plasma creatinine level:
             normal (age appropriate) or creatinine clearance ≥ 70mL/min/1.73m^2
          4. Subjects with ECOG performance score of 0 to 2.
          5. At least 3 months expected survival.
          6. Have a legal guardian sign the informed consent form.
        Exclusion criteria:
        Subjects will be excluded from the study if any of the following criteria is met.
          1. Subjects with Burkitt's leukemia.
          2. Received radiotherapy within 14 days prior to the first administration of the study
             drug.
          3. Subjects who have received chemotherapy within 2 weeks, prior to the first dose of
             CN201 (except for intrathecal chemotherapy and dexamethasone, and/or low-dose
             maintenance therapy except, e.g., vincristine, methotrexate) or within 5 half-lives of
             small molecule targeted drugs (which is shorter).
          4. Subjects who have received investigational drugs in other studies within 3 weeks prior
             to the first dose of CN201.
          5. Bone marrow blasts (primitive/naïve) B cells without CD19 expression.
          6. Acute or active chronic graft-versus-host disease (GVHD).
          7. Subjects receive GvHD prophylactical or therapeutic treatment with an
             immunosuppressive agent within 14 days prior to the first use of the study drug.
          8. Subjects with central nervous system (CNS) infiltration. Subjects with previous CNS
             infiltration that has been controlled with intrathecal therapy are allowed to be
             enrolled.
          9. Subjects with major organ surgery (excluding puncture biopsy) or significant trauma
             within 4 weeks prior to the first dose of CN201, or elective surgery during the study.
         10. Subjects who use of live attenuated vaccine within 4 weeks prior to the first dose of
             CN201.
               1. Exception: Use of an approved coronavirus disease 2019 (COVID-19) vaccine is
                  allowed, but the last dose of COVID-19 vaccine must be administered at least 2
                  weeks prior to the first dose of CN201.
               2. For active subjects enrolled in this study, COVID-19 vaccination is allowed after
                  8 weeks treatment have been completed and the safety data are abailable.
         11. Subjects who had adverse reactions prior to anti-tumor therapy that have not recovered
             to Grade ≤1 assessed by NCI-CTCAE Version 5.0 (except for toxicities such as alopecia
             judged by the Investigator as no safety risk).
         12. History or presence of clinically relevant CNS pathology such as epilepsy,
             hemorrhagic/ischemic stroke, severe brain injuries, dementia, Parkinson's disease,
             cerebellar disease, organic brain syndrome, or psychosis.
         13. Subjects with active infections that require intravenous anti-infective therapy prior
             to the first administration of the study drug or uncontrolled chronic infections.
         14. Subjects with a history of immunodeficiency, including history of any positive test
             result for human immunodeficiency virus (HIV) antibody.
         15. Subjects with chronic infection with hepatitis B, defined as having a positive
             hepatitis B surface antigen (HBsAg) test and/or detectable level of hepatitis B virus
             DNA at Screening, or hepatitis C infection, defined as having a positive hepatitis C
             virus (HCV) antibody test.
         16. Subjects with concomitant secondary malignancies (except adequately treated
             non-melanomatous skin cancers, ductal carcinoma in situ, superficial bladder cancer,
             prostate cancer, or in situ cervical cancers) are excluded unless a complete remission
             is achieved at least 5 years prior to study entry and no additional therapy is
             required during the study period.
         17. Subjects with a history of serious cardiovascular and cerebrovascular diseases,
             including but not limited to:
               1. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia
                  requiring clinical intervention, degree II-III atrioventricular block, or QTcF >
                  470 msec (female) or > 450 msec (male).
               2. Acute coronary syndrome, congestive heart failure, stroke, or other Grade 3 or
                  higher cardiovascular and cerebrovascular events within 6 months prior to the
                  first dose of CN201.
               3. New York Heart Association (NYHA) functional class ≥II or left ventricular
                  ejection fraction (LVEF) <50%.
         18. Subjects with uncontrollable space effusion (e.g. pleural effusion, abdominal
             effusion, pelvic effusion, etc.), as judged by the Investigator.
         19. Subjects with active autoimmune diseases that may relapse (e.g., systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid
             disease, vasculitis, psoriasis, etc.) or history of autoimmune disease with potential
             CNS involvement.
         20. Subjects who previously received immunotherapy and experienced Grade ≥3 immune-related
             AEs (irAEs).
         21. Subjects with known alcohol or drug dependence.
         22. Subjects with mental disorders.
         23. Female adolescents who conceive; adolescents of childbearing potential who do not wish
             to remain abstinent (avoid heterosexual intercourse) or who do not wish to use highly
             effective contraception (from the time of screening until 90 (±7) days after the last
             dose of CN201). During this period, females may not donate eggs.
         24. Subjects with any other condition or circumstance that would, in the discretion of the
             Investigator, make the subject unsuitable for participation in this clinical study.