A Study to Evaluate MK-1045 (CN201) in Participants With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (MK-1045-001/CN201-101)

Official title

An Open-Label, Dose Escalation Phase 1a Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of MK-1045 (CN201) in Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Overview

Researchers are looking for new ways to treat people with relapsed or refractory B-Cell Non-Hodgkin Lymphoma (B-NHL). B-cells are a type of white blood cells that make antibodies and help fight infections. Non-Hodgkin Lymphoma is a type of cancer in the lymphatic system causing enlarged lymph nodes and/or organs in belly or chest. Relapsed means a disease or condition comes back after treatment Refractory means a disease does not respond to treatment or stops responding to a treatment. MK-1045, the study medicine, is designed to treat relapsed or refractory B-NHL. MK-1045 is an immunotherapy, which is a treatment that helps the immune system fight cancer. This is the first study in which MK-1045 will be given to people. The goal of this study is to learn about: * The safety of MK-1045 and how well people tolerate it. * The highest dose of MK-1045 that is well tolerated. * How well MK-1045 works to treat relapsed or refractory B-NHL.

Interventions

• Drug MK-1045
  IV infusion

Primary outcome measures

• Number of Participants who Experience a Dose-limiting Toxicity (DLT) [Time frame: Up to ~28 Days]
• Number of Participants who Experience an Adverse Event (AE) [Time frame: Up to ~15 months]
• Number of Participants who Experience a Serious Adverse Events (SAE) [Time frame: Up to ~15 months]
• Number of Participants who Experience a Drug-related Adverse Event (DRAE) [Time frame: Up to ~15 months]
• Number of Participants who Experience an AE of Grade 3 or higher [Time frame: Up to ~15 months]
• Number of Participants who Experience an AE for Each Severity Grade from 1-5 [Time frame: Up to ~15 months]
• Number of Participants who Experience a SAE or Serious Drug-related AE [Time frame: Up to ~15 months]
• Number of Participants who Experience a Dose Modification Due to an AE or DRAE [Time frame: Up to ~15 months]
• Number of Participants who Withdraw from the Study due to an AE or DRAE [Time frame: Up to ~15 months]
• Number of Participants who Died due to an AE or DRAE [Time frame: Up to ~15 months]

Secondary outcome measures (12)

• Mean Change in Serum MK-1045 Concentration After Administration [Time frame: Baseline and up to 12 months]
• Area Under the Concentration-time Curve (AUC) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Area Under the Concentration-time Curve from Time 0 to 168 Hours Post Dose (AUC0-168) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 168 hours]
• Area Under the Concentration-time Curve from Time 0 to Last Quantifiable Concentration Post Dose (AUC0-last) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 168 hours]
• Maximum Concentration (Cmax) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Time to Maximum Concentration (Tmax) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Terminal Elimination Half-life (T1/2) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Clearance (CL) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Concentration at the End of Dosing Interval (Ctrough) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Area Under the Concentration-time Curve from Time 0 to the Dosing Interval (168 Hours) at Steady State (AUC0-tau) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 168 hours]
• Accumulatio Ratio Based on Cmax (RAC-Cmax) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]
• Accumulation Ratio Based on AUC0-tau (RAC_AUC0-tau) of MK-1045 [Time frame: Pre-dose and at designated time points post-dose up to 12 months]

Eligibility criteria

Inclusion/Exclusion Criteria:

Inclusion criteria

Inclusion Criteria include, but are not limited to:

• Has relapsed or refractory B-cell Non-Hodgkin's lymphoma (B-NHL) with disease history meeting 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, participants, excluding those treated with Chimeric antigen receptor T-cell (CAR-T) who cannot provide proof of pathologic immunohistochemistry CD19 positivity but have previous proof of CD20 positivity may be considered for enrollment after communication with the sponsor)

• Relapse is defined as the occurrence of progressive disease (PD) after complete response (CR) or partial response (PR) has been achieved after adequate treatment. Note: For DLBCL participants, relapse must occur after participants undergoing at least two lines of therapy; for other participants, 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: Participants 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); Participants who are not eligible for autologous hematopoietic stem cell transplantation (ASCT) and have relapsed PD after receiving ASCT; Participants who have failed on chimeric antigen receptor T cell (CAR-T) immunotherapy, but the first dose of the study intervention must be at least 3 months after discontinuation of CAR-T therapy, and CD19 positive expression is still present in tumor tissue.
• Has 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 magnetic resonance imaging (MRI)
• Has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2 and an estimated survival time of more than 3 months
• Has essentially normal: bone marrow function; coagulation function; liver function; kidney function; lung function; and heart function

Exclusion criteria

Exclusion Criteria include, but are not limited to:

• Has any other non-Hodgkin lymphoma (NHL) not listed in inclusion criteria
• Has been treated with anti-CD3/CD19 bispecific antibody (BsAb) prior to first dose of study intervention
• Has 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
• Has received anti-CD20 antibody or anti-CD19 antibody within 4 weeks prior to first use of the investigational drug
• Has received anti-tumor immunotherapy or other unlisted clinical study intervention within 4 weeks prior to the first dose of study intervention, or within 5 half-lives of the drug, whichever is shorter
• Has undergone any major organ surgery (excluding aspiration biopsy) or significant trauma within 4 weeks prior to the first dose of study intervention or those requiring elective surgeries during the study
• Has received systemic corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive agents within 14 days prior to the first dose of the study intervention, excluding the following agents: topical, ocular, intra-articular, intranasal, and inhaled corticosteroids, and short-term, prophylactic use of corticosteroids (e.g. to prevent radio contrast agent induced allergic reactions)
• Has 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 within 14 days prior to the first dose of study intervention
• Has had a live attenuated vaccines within 4 weeks prior to the first dose of study intervention
• Has a central nervous system (CNS) infiltration
• Has previous or concomitant CNS diseases, including epilepsy, severe brain injury, dementia, Parkinson's disease, cerebellar disorder, organic cerebellar syndrome, or mental diseases
• Has 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)
• Has uncontrolled active infections currently requiring systemic anti-infective therapy within 3 days prior to first dose
• Has active hepatitis B and/or hepatitis C. Participants who are positive for antibodies to hepatitis C virus (HCV). Participants who are hepatitis B surface antigen (HBsAg) positive are not allowed to enroll in the dose-escalation period; however, those who were hepatitis B surface antigen (HBsAg)-positive but hepatitis B Virus deoxyribonucleic acid (HBV DNA)-negative and adherent to entecavir antiviral therapy and who agreed to regular monthly monitoring of HBV DNA are allowed to enroll in the dose-expansion period
• Has a history of immunodeficiency, including testing positive for human immunodeficiency virus (HIV) antibody
• Has a history of serious cardiovascular and cerebrovascular disease, including but not limited to: severe cardiac rhythm or conduction abnormalities; 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; ≥ Class II cardiac function as per New York Heart Association (NYHA) functional class or LVEF < 50%; or clinically uncontrollable hypertension
• Has previous or current interstitial lung disease
• Has acute graft-versus-host disease (GVHD) or active chronic GVHD at present
• Has 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 participants who are at risks (e.g., organ transplant requiring immunosuppressive therapy). Participants 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).
• Has received immunotherapy with known Grade 3 or higher immune-related adverse events (irAEs)
• Has non-hematologic adverse reactions from prior anti-tumor therapy have not recovered to Grade ≤ 1 as assessed by National Cancer Institute NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 (excluding toxicities such as alopecia that are assessed by the investigator to have no safety risk)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 15 centers

• Fifth Medical Center of PLA General Hospital ( Site 0005) — Beijing
• Beijing Cancer hospital ( Site 0001) — Beijing
• The First Affiliated Hospital of Xiamen University ( Site 0011) — Xiameng
• Sun Yat-Sen University Cancer Center ( Site 0003) — Guangzhou
• The Fourth Hospital of Hebei Medical University. ( Site 0004) — Shijiazhuang
• Henan Cancer Hospital ( Site 0009) — Zhengzhou
• The First Affiliated Hospital of Zhengzhou University ( Site 0006) — Zhengzhou
• Jiangxi Cancer Hospital ( Site 0007) — Nanchang
• … and 7 more centers

Identifiers

NCT: NCT06189391 · 1045-001 · MK-1045-001 · CN201-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗