A Phase I Study of JLM019 Injection

Официальное название

A Phase I Study to Evaluate the Safety and Tolerability of JLM019 Injection in Patients With Advanced Malignancies

Обзор

This is a multicenter, single-arm, open-label, dose escalation phase (Part A) and dose expansion (Part B) study to evaluate the safety and tolerability of JLM019 Injection in patients with advanced malignancies. The study subjects are adults with advanced malignancies including advanced solid tumors or relapsed/refractory lymphoma. During the dose escalation phase, the dose escalation scheme is the accelerated titration in 0.001 - 0.2 mg/kg cohorts plus a traditional '3 + 3' design in 0.6 - 10 mg/kg cohorts, jointly in nine dose cohorts 0.001, 0.01, 0.05, 0.2, 0.6, 1.5, 3, 6 and 10 mg/kg. JLM019 Injection is intended to be administered once a week (QW). However, the dose and interval of administration may be adjusted based on the acquired PK, PD, and safety data. Each treatment cycle is 28 days.The repeated dose is tentatively scheduled to be administered once weekly until one of the following occurs: disease progression, intolerable toxicity, requirement for new antitumor therapy, withdrawal of informed consent form, death, loss to follow-up, or other protocol-specified discontinuation conditions. Safety profile, DLT, MTD and RED of JLM019 Injection shall be assessed during and after treatment, with PK, PD, immunogenicity and Efficacy analyzed correspondingly.

Подробное описание

1\. Dose Escalation Rules

1. If one Grade ≥ 2 treatment-emergent adverse event (TEAE) during the DLT observation period after the first dose at any dose level in Part A Dose Escalation will Add one more enrolled participant. If the supplementary enrolled subject also experiences ≥Grade 2 treatment-emergent adverse event will trigger the transition from accelerated titration to the traditional '3 + 3' cohort design. 2. At the '3 + 3' dose escalation stage, a sentinel cohort will be employed. If no DLTs occur in the sentinel cohort within 14 days after the drug administration, the other two patients will be enrolled at once in this dose group. If DLTs occur in the sentinel cohort, the other two patients will also be enrolled sequentially. 3. At the '3 + 3' dose escalation stage,

1. If the first 3 patients at this dose level experience no DLTs during the observation period, the dose will be escalated. 2. If 1 of the first 3 patients experienced DLTs or 2 of the first 3 patients of a cohort have Grade ≥ 2 CRS or neurotoxicity, another 3 patients will be enrolled in this group again, and dose escalation will be evaluated based on these 6 patients: 3. If 1 of 6 patients experience DLTs, the dose will be escalated. 4. If ≥ 2 of 6 patients experience DLTs, the dose escalation will be stopped. 5. If ≥ 2 of the first 3 patients experienced DLTs, the dose escalation will be stopped. 4. If MTD is reached at the starting dose level, a lower dose level will be considered. 5. Upon completion of DLT observation for each dose level, SRC will determine whether to terminate dose escalation or continue for further escalation or expand the dose groups based on a comprehensive review of the collected data. 6. The Recommended Expansion Dose (RED) will be determined based on the assessments of safety, efficacy, and PK data, regardless of whether the MTD is achieved.

2\. Statistical Analysis 2.1 Safety Analysis AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be graded according to NCI CTCAE v6.0. AEs will be summarized by treatment group, System Organ Class (SOC), and Preferred Term (PT). Summaries will include (but not limited to): number of cases and incidence rates for all AEs, drug-related AEs, serious AEs (SAEs), drug-related SAEs, AEs leading to treatment discontinuation, and fatal AEs. For clinical safety assessments (laboratory tests, vital signs, physical examinations, 12-lead ECGs, etc.), treatment related changes from baseline will be described. Treatment-emergent abnormal findings will be listed in tables. During the dose-escalation phase, the incidence of DLTs will be calculated for each dose cohort.

2.2 PK Analysis Drug concentration data in peripheral blood will be analyzed by dose cohort according to scheduled PK sampling time-points. Individual and mean concentration-time profiles will be plotted for each dose cohort using both linear and semi-logarithmic scales. For summary statistics (e.g., mean concentration) and mean profile plots: Scheduled PK sampling time will be used. For individual patient concentration-time curves: Actual PK sampling time will be used.

PK parameters including: Cmax, Tmax, t1/2, AUC0\~inf, AUC0\~t, CL/F, and Vz/F, will be analyzed by using non-compartmental analysis (NCA) for each dose cohort. Descriptive statistics will include number of subjects (n), arithmetic mean, standard deviation (SD), coefficient of variation (CV%), minimum, and maximum. For key parameters (e.g., Cmax and AUC0-inf), geometric mean and geometric CV% will also be reported.

2.3 PD Analysis Descriptive statistical methods will be used to analyze PD parameters by treatment groups. Time-course profiles of PD markers will be plotted.

2.4 ADA Analysis Descriptive summaries will be provided for the time and the proportion of ADA-positive subjects following investigational drug administration. ADA positive subjects will undergo Nab testing, and the time and incidence of Nab occurrence will be summarized.

2.5 Efficacy Analysis ORR and DCR will be reported as the number and percentage of subjects in each dose cohort, with 95 % confidence intervals (CIs) estimated by using the Clopper-Pearson method. For time-to-event endpoints (PFS, DOR, OS), median survival duration and corresponding 95 % CIs will be estimated for each dose cohort by using the Kaplan-Meier method. Kaplan-Meier survival curves will be plotted for the event occurrence over the time.

Вмешательства

• Биопрепарат JLM019 Injection
  The JLM019 Injection will be administered via intravenous (IV) infusion at dose levels of 0.001, 0.01, 0.05, 0.2, 0.6, 1.5, 3, 6, and 10 mg/kg. Each IV infusion must last at least 30 min. The repeated dose is tentatively scheduled to be administered once weekly until one of the following occurs: disease progression, intolerable toxicity, requirement for new antitumor therapy, withdrawal of informed consent form, death, loss to follow-up, or other protocol-specified discontinuation conditions. (N

Первичные конечные точки

• Number of participants with reported Dose-limiting toxicity (DLT) [Срок оценки: Within 28 days after the first dose]
• Rate of adverse events [Срок оценки: Up to 3 years]
• Determine the recommended dose for combination for JLM019 injection [Срок оценки: Up to 3 years]

Вторичные конечные точки (9)

• Determination of JLM019 concentrations [Срок оценки: Up to 12 months]
• Detection of anti-JLM019 antibodies in serum [Срок оценки: Up to 12 months]
• Determination of detailed blood lymphocyte subsets [Срок оценки: Up to 12 months]
• Determination of cytokines in blood [Срок оценки: Up to 12 months]
• Objective response rate [Срок оценки: Up to 12 months]
• Disease control rate [Срок оценки: Up to 12 months]
• Progression-free survival [Срок оценки: Up to 15 years]
• Duration of response [Срок оценки: Up to 15 years]
• Overall survival [Срок оценки: Up to 15 years]

Критерии участия

Критерии включения

• Eighteen years of age or older;
• Patients with histopathologically or cytologically confirmed advanced solid tumors (AST) or relapsed/refractory (r/r) Hodgkin's/Non-Hodgkin's lymphomas (HL/NHL, including transformed lymphomas):

• AST subtypes include but are not limited: colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), gastric cancer (GC), ovarian cancer (OV), renal cell carcinoma (RCC), melanoma, biliary tract cancer (BTC), alveolar soft part sarcoma (ASPS), etc.
• HL/NHL subtypes include but are not limited: classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), etc.
• Measurable disease as defined as:

• AST: At least one tumor lesion ≥ 10 mm in the longest diameter as assessed by computed tomography (CT);
• HL/NHL: Fluorodeoxyglucose (FDG) avid disease by positron emission tomography (PET) and ≥ 1 lesion > 15 mm in the longest diameter by > 10 mm in the short axis, as assessed by CT;
• Patients with the following molecular profiles will be prioritized for enrollment:

• High tumor T-cell infiltration (e.g., elevated T-cell GEP score);
• TMB > 10 mut/Mb、MSI-H/dMMR status or POLE/POLD1 mutations. Absence of β2M and JAK1/JAK2 loss-of-function mutations.
• Submission of tumor biopsy representative of the current disease, which may consist of any of the following:

• Archived formalin-fixed paraffin-embedded (FFPE) tissue block;
• At least 15-20 slides of tumor tissue from an FFPE block suitable for immunohistochemistry (IHC), including ≥ 10 % tumor content per section with ≥ 20 mm2 of evaluable tissue which may include ≤ 50 % tumor adjacent tissue;
• A fresh tumor biopsy obtained by surgical excision or core needle procedure prior to the first dose of JLM019 Injection;
• For patients with accessible tumors, willingness to undergo on-study biopsy as scheduled in the protocol;
• Eastern Cooperative Oncology Group (ECOG) performance status grade 0\~1;
• Life expectancy ≥ 3 months estimated by the Investigator;
• Recovery to Grade ≤ 1 for any non-laboratory toxicity resulting from previous anticancer therapy prior to the first dose of investigational product (except alopecia, hearing loss, Grade ≤ 2 neuropathy, or endocrinopathy managed with replacement therapy);
• Adequate baseline hematologic, renal, hepatic, and cardiac function as defined by:

• Lymphocyte ≥ 0.5 × 109/L；
• ANC ≥ 1.5 × 109/L;
• Platelet count (PLT) ≥ 100 × 109/L;
• Hemoglobin (HGB)≥ 90 g/L (no packed red blood cell transfusion within the prior 2 weeks);
• Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for patients with Gilbert's disease;
• Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2, as calculated by the Modification of Diet in Renal Disease (MDRD) formula;
• ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN if there is evidence of hepatic involvement by malignant disease);
• International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the patient is receiving anticoagulant therapy in which PT or aPTT is within therapeutic range of intended use of anticoagulants;
• High sensitivity cardiac troponin I (hs-cTnI) and N-terminal pro B-type natriuretic peptide (NT-proBNP) ≤ ULN (asymptomatic abnormalities may be permitted after clearance by cardiology consultation).
• All patients and their partners must have no plans for conception from screening period and during the trial, and agree to practice effective contraception during the trial and for 4 months after the last dose of JLM019.
• Able to participate and willing to give written informed consent form.

Критерии исключения

• Allergy to JLM019 Injection components;
• History of Grade 4 infusion-related, anaphylactic or allergic reaction to any previous monoclonal antibody or other Fc-based protein therapy;
• Experienced any cardiovascular immune-related adverse event (irAE), or discontinued from that treatment due to a Grade 3 or higher irAE in previous ICI therapy;
• Any serious or uncontrolled health conditions listed below:

• Patients with concurrent infections requiring intravenous antimicrobial therapy within the past 2 weeks, or with unexplained fever (body temperature ≥ 37.5 °C);
• History of vascular diseases within the past 6 months (including myocardial infarction, unstable angina, cerebrovascular diseases, and peripheral arterial or aortic diseases);
• Uncontrolled hypertension (defined as systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg on at least two separate occasions after antihypertensive treatment);
• Individuals with active thrombosis, active bleeding, or pathological conditions associated with high bleeding risk (such as coagulation disorders);
• Has an active autoimmune disease that has required systemic treatment (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment;
• Any serious or uncontrolled cardiovascular condition, including but not necessarily limited to:

• Any history of myocarditis of any etiology;
• History of New York Heart Association Class III or IV congestive heart failure, myocardial infarction, unstable angina, cerebrovascular accident, cardiac hospitalization, or other acute uncontrolled heart disease within 6 months of scheduled C1D1;
• Left ventricular ejection fraction < 45 % on screening echocardiogram;
• Any clinically significant findings on screening EKG such as atrial or ventricular arrythmia (other than sinus tachycardia) or AV conduction abnormality such as left bundle branch block (such patients may be enrolled after cardiology clearance and Sponsor approval);
• History of (non-infectious) pneumonitis / interstitial lung disease or current pneumonitis / interstitial lung disease;
• Presence of any active central nervous system (CNS; brain or leptomeningeal) metastases. Solid tumor patients with CNS metastases are eligible if previously treated and there is no magnetic resonance imaging (MRI) evidence of progression for ≥ 8 weeks after treatment is complete and within 28 days prior to first dose of JLM019 Injection;
• Prior organ allograft or allogeneic hematopoietic stem cell transplantation (HSCT). Lymphoma patients ≥ 3 months post-HSCT with no evidence of active graft versus host disease may be eligible upon approval by the Investigator or Sponsor;
• Receipt of any of the following within the timeframes indicated, before first scheduled dose of JLM019 Injection:

• Checkpoint inhibitors, including PD-(L)1 (e.g., pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab), CTLA-4 (e.g., ipilimumab, tremelimumab) and Lag-3 (e.g., relatlimab), or costimulatory agonists (including but not limited to CD28, CD134 (OX40), CD137 (4-1BB)): 3 months (135 days for atezolizumab);
• Chemotherapy, small molecule anticancer agents (e.g., kinase inhibitors), or radiation: 2 weeks. Note: for lung cancers or mesotheliomas, radiation therapy to the lung that is > 30 Gy within 6 months;
• Other monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, antibody-like drugs, cytokines, cell therapies, or radio immunoconjugates: 4 weeks (2 weeks permissible with documented disease progression and approval by the medical monitor or Sponsor);
• Currently participating in another clinical trial or has participated in another clinical trial within 4 weeks prior to the first dose of the investigational study treatment. Note: Patients who have entered the follow-up phase of another study may be enrolled if at least 4 weeks have elapsed since their last dose of study treatment;
• Any condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone or equivalent) or other immunosuppressive medications within 14 days of the first dose of JLM019 Injection. Inhaled, intranasal or topical corticosteroids or adrenal replacement doses of corticosteroids are permitted in the absence of active autoimmune disease;
• Received a live or live-attenuated vaccine within 30 days prior to the first dose of JLM019 Injection. Note: Administration of inactivated vaccines is allowed;
• Received radiotherapy within 2 weeks of start of study treatment or had a history of radiation pneumonitis. Note: Patients must have recovered from all radiation-related toxicities, not required corticosteroids, and show no evidence of radiation pneumonitis. A 1-week washout period is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease;
• Any second malignancy active within the previous 3 years( (except adequately treated carcinoma in situ of cervix, basal cell carcinoma or squamous cell skin carcinoma));
• Patients with a history of AIDS, syphilis, or active hepatitis \[For hepatitis B: positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV-DNA copy number above the upper limit of quantification; for hepatitis C: positive HCV antibody and HCV RNA copy number above the upper limit of quantification\].
• Pregnancy or lactation, and a woman of childbearing potential (WOCBP) who has a positive pregnancy test (within 7 days) prior to treatment;
• Patients deemed unsuitable for participation in this study at the Investigator's discretion.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking Union Medical College Hospital — Пекин

Идентификаторы

NCT: NCT07623850 · JLM019-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗