A Phase Ib/II Study of CN201 in Precursor B-cell Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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This is a multicenter, open-label, Phase Ib/II study in subjects with precursor B-cell acute lymphoblastic leukemia (B-ALL). This study is designed in 2 parts as described below: Phase Ib (dose escalation and expansion) and Phase II. 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. For Phase Ib, the dose escalation employs Bayesian optimal interval (BOIN) design. Administered by IV infusion, once every week (QW), will be evaluated to determine the MTD and/or RP2D of CN201. After RP2D is determined in Phase Ib, the Phase II study will be initiated to further evaluate the safety, tolerance, PK and PD characteristics, and anti-tumor activity of CN201 in subjects with B-ALL. Simon's two-stage minimax design will be employed to preliminarily explore the efficacy of CN201 in treatment of R/R B-ALL.

Official Title
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An Open-label, Multi-center Phase Ib/II Study of CN201 in Subjects With Precursor B-cell Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: CN201


Participation Criteria
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Eligibility Criteria
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Adult cohort: Inclusion criteria: Subjects are eligible to be included in the study only if all the following criteria are met. Subjects aged ≥18 years old on the day of signing the informed consent form. 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. Subjects with ECOG performance score of 0 to 2. At least 3 months expected survival. 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) 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: Established hormonal contraception (with approved oral contraceptive pills, long-acting implantable hormones, injectable hormones). A vaginal ring or an intrauterine device (IUD). 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). 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. 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. 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. 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. Subjects with Burkitt's leukemia. Subjects who have received bbbanti-CD19 therapy within 3 months prior to the first dose of CN201. Subjects who have received allogeneic HSCT within 12 weeks prior to the first dose of CN201. Subjects who have received autologous HSCT within 6 weeks prior to the first dose of CN201. 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. Subjects who have received immunotherapy within 3 weeks prior to the first dose of CN201. Subjects who have received other investigational agents (not yet approved by any regulatory agency) within 3 weeks prior to the first dose of CN201. Subjects who have received prior treatment with CAR-T within 3 months prior to the first dose of CN201. 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. Subjects who use of live attenuated vaccine within 4 weeks prior to the first dose of CN201 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. 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. 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). 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. 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. Have a serious uncontrolled active infection. Subjects with a history of immunodeficiency, including history of any positive test result for human immunodeficiency virus (HIV) antibody. 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. Subjects with current or previous interstitial lung disease. 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. Subjects with a history of serious cardiovascular and cerebrovascular diseases, including but not limited to: 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). 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. New York Heart Association (NYHA) functional class ≥II or left ventricular ejection fraction (LVEF) <50%. Subjects with uncontrollable space effusion (e.g. pleural effusion, abdominal effusion, pelvic effusion, etc.), as judged by the Investigator. 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. Any active acute Graft-versus-Host Disease (GvHD), Grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment. Any systemic therapy against GvHD within 2 weeks before start of CN201. Subjects who previously received immunotherapy and experienced Grade ≥3 immune-related AEs (irAEs). Subjects with known alcohol or drug dependence. Subjects with mental disorders or other conditions that pose high noncompliance risks. 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. Subjects aged <18 years old on the day of signing the informed consent form. 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. 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 Subjects with ECOG performance score of 0 to 2. At least 3 months expected survival. 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. Subjects with Burkitt's leukemia. Received radiotherapy within 14 days prior to the first administration of the study drug. 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). Subjects who have received investigational drugs in other studies within 3 weeks prior to the first dose of CN201. Bone marrow blasts (primitive/naïve) B cells without CD19 expression. Acute or active chronic graft-versus-host disease (GVHD). Subjects receive GvHD prophylactical or therapeutic treatment with an immunosuppressive agent within 14 days prior to the first use of the study drug. Subjects with central nervous system (CNS) infiltration. Subjects with previous CNS infiltration that has been controlled with intrathecal therapy are allowed to be enrolled. 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. Subjects who use of live attenuated vaccine within 4 weeks prior to the first dose of CN201. 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. 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. 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). 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. Subjects with active infections that require intravenous anti-infective therapy prior to the first administration of the study drug or uncontrolled chronic infections. Subjects with a history of immunodeficiency, including history of any positive test result for human immunodeficiency virus (HIV) antibody. 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. 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. Subjects with a history of serious cardiovascular and cerebrovascular diseases, including but not limited to: 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). 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. New York Heart Association (NYHA) functional class ≥II or left ventricular ejection fraction (LVEF) <50%. Subjects with uncontrollable space effusion (e.g. pleural effusion, abdominal effusion, pelvic effusion, etc.), as judged by the Investigator. 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. Subjects who previously received immunotherapy and experienced Grade ≥3 immune-related AEs (irAEs). Subjects with known alcohol or drug dependence. Subjects with mental disorders. 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. 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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CN201<br>By study design, planned target CN201 dose levels in adults are 600μg, 1200 μg, 2500 μg , 5000 μg, 10000μg, and 20000μg. Planned target CN201 dose levels in pediatric subjects are 5000μg and 10000μg. Consider enrollment of pediatric subjects only if safety data are available for the corresponding target dose group in adults which demonstrates safety. Subjects will receive CN201 by intravenous infusion (IV), once per week, four weeks per treatment cycle. | Drug: CN201<br>* The treatments include 2 cycles of induction treatment, 3 cycles of consolidation treatment, and up to 7 cycles of maintenance treatment. During the Treatment Period, subjects will receive CN201 by intravenous (IV) infusion once every week (QW), 4 weeks per treatment cycle. The subjects will receive 2 cycles of CN201 for induction. After induction treatment, the drug is discontinued for 2 weeks (treatment-free interval) before consolidation therapy is started, and each subsequent treatment cycle (4 weeks/treatment cycle) is followed by a 2-week treatment-free interval. Responders to induction treatment will continue to receive 3 cycles of consolidation treatment, followed by an additional up to 7 cycles of maintenance treatment, or until intolerable toxicity, disease progression, withdrawal of informed consent, loss to follow-up, receipt of other antitumor therapy, or death, whichever occurs first.<br>* Other names: CN201 for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall incidence and severity of adverse events measured by NCI-CTCAE 5.0 | All AEs will be graded according to NCI-CTCAE Version 5.0. | through study completion, an average of 1 year | 
| Incidence of the dose-limiting toxicity | In the present study, the DLT observation period is 28 days following the first dose of CN201 in Cycle 1. All AEs will be graded according to NCI-CTCAE Version 5.0. | 4 weeks | 
| The maximum tolerated dose | The MTD will be determined based on the occurrence rate of the DLT. If a DLT is observed in 2 or more of 6 subjects, the MTD will have been exceeded. The MTD is defined as the highest dose in which 1/6 or less subjects experience a DLT. If fewer than 2 of 6 evaluable subjects at the highest dose level tested experience a DLT, this dose level will be declared the maximum administered dose . | through study completion, an average of 1 year | 
| The recommended phase II dose | The SMC will be responsible for determining the RP2D, taking into account all safety, efficacy, PK, PD, and ADA data. | through study completion, an average of 1 year | 
| The rate of complete response within two cycles of treatment with CN201 | Response within the first 2 treatment cycle was assessed. Response was evaluated using imageological diagnosis , and bone marrow biopsy. Complete response is defined as the disappearance of all evidence of disease. | 8 weeks |