A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of CN201

Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Clinical Trial

Official title:

A Single-Arm, Open-Label, Dose Escalation Phase 1a Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of CN201 in Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06189391
• Other study ID #: CN201-101
• Status: Recruiting
• Phase: Phase 1
• Start date: March 4, 2021
• Est. completion date: December 1, 2025

Study information

• Verified date: December 2023
• Source: Curon Biopharmaceutical (Shanghai) Co.,Ltd
• Contact: yuqin Song, MD
• Phone: 8610-88196922
• Email: songyuqin622[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to provide a basis for further clinical development of CN201.

Description:

This study is the first-in-human clinical trial of CN201 to evaluate the safety, tolerability, pharmacokinetic (PK) profile and preliminary efficacy of CN201 in patients with relapsed or refractory B-NHL. This study will provide a basis for further clinical development of CN201.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion/Exclusion Criteria:

Inclusion Criteria (Patients who meet all of the following criteria may be enrolled in this clinical study)

1. Males or females aged = 18 to = 75 years.

2. Patients with relapsed or refractory B-NHL. These patients disease history must meet the following World Health Organization (WHO) diagnostic subtypes of B-NHL that are CD19-positive in pathologic Immunohistochemistry test: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) (Grade I to III), marginal zone lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, and transformed large B-cell lymphoma (During the dose-escalation phase, patients other than those treated with CAR-T who cannot provide proof of pathologic immunohistochemistry CD19 positivity but have previous proof of CD20 positivity may be considered for enrollment after discussion with the sponsor.).

• "Relapse" is defined as the occurrence of PD (progression at primary site or new onsets at other sites) after complete response (CR) or partial response (PR) has been achieved after adequate treatment. Note: For DLBCL patients, relapse must occur after patients undergoing at least two lines of therapy; for other patients, they must undergo at least one line of therapy.

• "Refractory" is defined as a situation that there is no standard of care available or that it is not applicable to use standard of care at this stage, including:

1. Patients who are unresponsive to standard of care (e.g., monotherapy or combination therapy containing anti-CD20 monoclonal antibody) and whose best response to standard therapy is PD or stable disease (SD).

2. Patients who are not eligible for autologous hematopoietic stem cell transplantation (ASCT) and have relapsed PD after receiving ASCT.

3. Patients who have failed on chimeric antigen receptor T cell (CAR-T) immunotherapy, but the first dose of the IMP must be at least 3 months after discontinuation of CAR-T therapy, and CD19 positive expression is still present in tumor tissue.

3. Patients with at least one evaluable tumor lesion per the Lugano 2014 criteria, i.e., a lymph node lesion > 15 mm in long diameter or an extranodal lesion > 10 mm in long diameter according to computed tomography (CT) cross-sectional imaging or MRI.

4. Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of = 2 and an estimated survival time of more than 3 months.

5. Patients with essentially normal bone marrow function (no blood transfusion within 14 days prior to first dose), including: PLT = 75 × 10 ^ 9/L, absolute neutrophil count (ANC) = 1.5 × 10 ^ 9/L, absolute peripheral blood lymphocyte count (ALC) = 200/µL, and hemoglobin (Hgb) = 9.0 g/dL.

6. Patients with essentially normal coagulation function: activated partial thromboplastin time (APTT) = 1.5 × upper limit of normal (ULN); international normalized ratio (INR) = 1.5 × ULN.

7. Patients with essentially normal function of liver, kidney, lung, and heart function:

1. Liver function: serum total bilirubin = 1.5 × ULN (= 3.0 × ULN unless there is evidence of Gilbert's syndrome); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 × ULN (= 5.0 × ULN if liver function is affected by any secondary changes caused by tumor);

2. Serum creatinine = 1.5 × ULN or estimated creatinine clearance = 50 mL/min (calculated according to the criteria used by the actual measurement center);

3. Echocardiography: left ventricular ejection fraction (LVEF) = 50%, no pericardial effusion;12-lead electrocardiogram (ECG) results: no clinically significant ECG abnormalities [atrial fibrillation of any grade, type II atrioventricular block of second degree, or third-degree atrioventricular block, or QTcF > 470 msec (female) or > 450 msec (male); other uncontrolled symptomatic arrhythmia];

4. No clinically significant pleural effusion and/or fluid in the abdomen;

5. Oxygen saturation > 92% (without oxygen inhalation).

8. Patients must provide informed consent prior to the initiation of the study and voluntarily sign a written ICF.

9. Female patients of childbearing potential must have a negative blood or urine pregnancy test within 7 days prior to the first dose of the IMP; patients of childbearing potential (males and females) must agree to use reliable methods of contraception (hormonal or barrier methods or sexual abstinence) with their partner after signing the ICF until 90 days after the last dose.

Exclusion Criteria (Patients who meet any of the following exclusion criteria will not be included in this study)

1. Patients with any other non-Hodgkin lymphoma (NHL) not listed in inclusion criteria (2).

2. Patients treated with anti-CD3/CD19 bispecific antibody (BsAb) prior to first dose of IMP (After discontinuing treatment with the IMP, subjects in the 2.5 µg/dose and 5 µg/dose groups of this study may have one opportunity to participate in the higher dose group after eluted for 5 half-lives of the drug, provided that the patient will benefit from the high dose group as assessed by the investigator, and that the participation is in accordance with the patient's wishes, and approved by the Sponsor).

3. Patients who have received chemotherapy, endocrine therapy , radiotherapy (palliative radiotherapy 2 weeks prior to the first administration of the investigational drug), or biologic therapy, and small molecule targeted agents within 2 weeks prior to the first administration of the investigational drug or within 5 half-lives of the drug, whichever is shorter. Patients who have received anti-CD20 antibody or anti-CD19 antibody within 4 weeks prior to first use of the investigational drug.

4. Patients who have received anti-tumor immunotherapy or other unlisted clinical IMP within 4 weeks prior to the first dose of IMP, or within 5 half-lives of the drug, whichever is shorter.

5. Patients who have undergone any major organ surgery (excluding aspiration biopsy) or significant trauma within 4 weeks prior to the first dose of the IMP, or those requiring elective surgeries during the study.

6. Patients who have received systemic corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive agents within 14 days prior to the first dose of the IMP, excluding the following agents: topical, ocular, intra-articular, intranasal, and inhaled corticosteroids, and short-term, prophylactic use of corticosteroids (eg, to prevent radio contrast agent induced allergic reactions).

7. Patients who have used immunomodulatory agents, including but not limited to thymosin, interleukin-2 (IL-2), interferon (IFN) and anti-tumor Chinese patent drugs or Chinese herbal medicines, etc., within 14 days prior to the first dose of the IMP.

8. Patients who have used live attenuated vaccines within 4 weeks prior to the first dose of the IMP.

9. Patients with central nervous system (CNS) infiltration.

10. Patients with previous or concomitant CNS diseases, including: epilepsy, hemorrhagic/ischemic stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disorder, organic cerebellar syndrome, mental diseases, etc.

11. Patients with prior or concomitant malignancies (except cured basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, prostatic intraepithelial neoplasia, and other tumors that have been clinically cured for 5 years as assessed by the investigator).

12. Patients with uncontrolled active infections currently requiring systemic anti-infective therapy within 3 days prior to first dose.

13. Patients with active hepatitis B and/or hepatitis C. Patients who are positive for antibodies to hepatitis C virus (HCV). Patients with hepatitis B surface antigen (HBsAg) was not allowed to enroll in the dose-escalation period; however, those who were hepatitis B surface antigen (HBsAg)-positive but HBVDNA-negative and adherent to entecavir antiviral therapy and who agreed to regular monitoring of HBVDNA were allowed to enroll in the dose-expansion period.

14. Patients with a history of immunodeficiency, including those who are tested positive for human immunodeficiency virus (HIV) antibody.

15. Patients with a history of serious cardiovascular and cerebrovascular disease, including but not limited to:

1. Patients with severe cardiac rhythm or conduction abnormalities;

2. Patients with 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;

3. Patients with = Class II cardiac function as per New York Heart Association (NYHA) functional class or LVEF < 50%;

4. Patients with clinically uncontrollable hypertension.

16. Patients with previous or current interstitial lung disease.

17. Patients with acute graft-versus-host disease (GVHD) or active chronic GVHD at present.

18. Patients with active or history of autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, vasculitis, psoriasis, etc.) that may relapse, or patients who are at risks (e.g., organ transplant requiring immunosuppressive therapy). However, patients with the following diseases are allowed to be further screened for enrollment: hypothyroidism managed with hormone replacement therapy only, and skin diseases not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia).

19. Patients who have received immunotherapy and experienced Grade 3 or higher immune-related adverse events (irAEs).

20. Patients whose non-hematologic adverse reactions from prior anti-tumor therapy have not recovered to Grade = 1 as assessed by NCI-CTCAE Version 5.0 (excluding toxicities such as alopecia that are assessed by the investigator to have no safety risk).

21. Patients with known alcohol or drug dependence.

22. Patients with mental disorders or poor protocol compliance.

23. Pregnant or lactating women.

24. Patients that are considered ineligible for this study by the investigator for other reasons.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Intervention

Drug:
• CN201
In fixed dosing group, patients will be administered with CN201 by intravenous infusion on Day 1 of each week for 3 consecutive weeks, followed by 1 week off for 4 weeks as a treatment cycle. Patients in step-up dosing group will be administered with CN201 by intravenous infusion on Day 1 of each week for 3 consecutive weeks (without treatment off week). Patients who complete 4 treatment cycles and remain in complete response (CR) or partial response (PR) may also be considered by the investigator for 2-weekly dosing (Q2W, window: -3 days, 4 weeks in a treatment cycle), which allows further comparative observation of the long-term efficacy and safety of Q2W. Treatment will be continued untill confirmed disease progression, intolerable toxicity, withdrawal of consent, patient being lost to follow-up, receipt of other antitumor therapy, death or study termination by sponsor, whichever occurs earlier, or up to 12 months in the absence of disease progression.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Curon Biopharmaceutical (Shanghai) Co.,Ltd

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence and profile of dose-limiting toxicity (DLT).	The toxicities occurring within 28 days (i.e., DLT observation period in Group A, fixed dosing) or 21 days (DLT observation period in step-up dosing group) after the first dose will be defined as DLTs in the discretion of the investigator as possibly, probably or definitely related to the IMP (Investigational Medicinal Product).	28 or 21 days after the first dose
Primary	Overall frequency of adverse events (AEs).	An AE is defined as any untoward medical event that occurs after a subject receives the investigational drug, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the investigational drug.	From the time the patient signs the ICF until the end of the safety visit period, assessed up to 15 months.
Primary	Overall frequency of serious adverse events (SAEs).	An SAE refers to an untoward medical occurrence such as death, life-threatening event, permanent or serious disability or loss of function, need for hospitalization or prolongation of hospitalization after the subject receives the IMP, and congenital abnormalities or birth defects.	From the time the patient signs the ICF until the end of the safety visit period, assessed up to 15 months.
Secondary	Changes in serum CN201 concentration after administration	Assess the changes in serum CN201 concentration after treatment with CN201	up to 12 months
Secondary	Area under the concentration-time curve (AUC) after administration	Assess the AUC after treatment with CN201	up to 12 months
Secondary	Maximum concentration (Cmax) after administration	Assess the Cmax after treatment with CN201	up to 12 months
Secondary	Time to maximum concentration (Tmax) after administration	Assess the Tmax after treatment with CN201	up to 12 months
Secondary	Terminal elimination half-life (T1/2) after administration	Assess the terminal elimination half-life (T1/2) after treatment with CN201	up to 12 months
Secondary	Number of B cells and T cells in peripheral blood after administration	Assess the number of B cells and T cells in peripheral blood after treatment with CN201	up to 12 months
Secondary	Level of T cell activation and proliferation after administration	Assess the T cell activation and proliferation after treatment with CN201	up to 12 months
Secondary	Level of cytokines in peripheral blood after administration	Assess the level of cytokines after treatment with CN201	up to 12 months
Secondary	Anti-drug antibodies (ADA)	Assess the ADA after treatment with CN201	up to 15 months
Secondary	Tumor objective response rate (ORR)	Assess the Overall Response Rate (ORR) after treatment with CN201	up to 15 months
Secondary	Duration of response (DOR)	Assess the Duration of response (DOR) after treatment with CN201	up to 15 months