A Phase I Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Characteristics of HLX37 (Recombinant Human Bispecific Antibodies Against PD-L1 and VEGF) in Patients With Advanced/Metastatic Solid Tumors
Overview
- Phase
- Early Phase 1
- Intervention
- HLX37
- Conditions
- Not specified
- Sponsor
- Shanghai Henlius Biotech
- Enrollment
- 254
- Locations
- 2
- Primary Endpoint
- The Dose-Limiting Toxicity (DLT) of HLX37 within 21 days after the first Administration
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This study is an open-label first-in-human phase I clinical study to evaluate the safety, tolerability, and pharmacokinetic characteristics of HLX37 in patients with advanced/metastatic solid tumors.
Detailed Description
This study is an open-label first-in-human phase I clinical study to evaluate the safety, tolerability , and pharmacokinetic characteristics of HLX37 with escalated doses in the treatment of patients with advanced/metastatic solid tumors. In Phase Ia Part 1of this study, a 3 + 3 dose escalation method will be adopted, and the patients will be administered with HLX37 at different doses via intravenous infusion. The DLT observation period lasts for 3 weeks after the first administration of HLX37. After the DLT observation period of the single-drug ramp-up 20mg/kg dose group ended and the SRC safety assessment was conducted, that is Initiate the Phase Ia Part2 of this study to conduct HLX37 in patients with advanced non-small cell lung cancerThe dosage of combined chemotherapy is increasing. The 3+3 dose escalation method will be adopted, and the subjects will receive different doses. Intravenous infusion administration of HLX37 in combination with chemotherapy (tentatively 10 mg/kg, 20 mg/kg, 30 mg/kg) Or other doses of HLX37 combined with chemotherapy, administered intravenously at Q3W. DLT observation period 3 weeks after the first administration of HLX37 in combination with chemotherapy. In phase Ib of this study, The Safety Review Committee will recommend dose groups for expansion based on the safety, efficacy and PK data of the dose escalation phase.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Selection criteria
- •Before the trial, fully understand the content, process and possible adverse reactions of the trial, sign the informed consent form, voluntarily participate in the trial, and be able to complete the research in accordance with the requirements of the trial protocol.
- •At the time of signing the ICF, the applicant must be at least 18 years old and no more than 75 years old, with no gender restrictions.
- •part 1 of Stage Ia enrolled subjects with advanced or metastatic solid tumors confirmed by histology or cytology, who had failed at least one standard systemic treatment in the advanced or metastatic stage of the disease (subjects who had received neoadjuvant or adjuvant therapy, if disease progression or recurrence occurred within 6 months after the end of treatment) Then this treatment plan will be regarded as a failure of standard treatment, or there is currently no effective standard treatment method.
- •Part 2 of stage Ia enrollment confirmed by histology or cytology Locally advanced (stage ⅢB/ⅢC) or metastatic (stage IV) NSCLC that is not suitable for radical treatment (complete surgical resection, concurrent/sequential chemoradiotherapy) (according to the 8th edition of lung cancer TNM staging by the Union for International Cancer Control and the American Joint Committee on Cancer AJCC), and should meet the following criteria:
- •Subjects without targeted driver gene alterations (AGA) :
- •For non-squamous NSCLC subjects, there must be previous test results confirming negative EGFR and ALK gene alterations. If there are no previous EGFR and ALK test results, the subjects are required to undergo relevant tests at the research center. For subjects with squamous NSCLC, if the previous EGFR and/or ALK gene status is unknown, corresponding tests are not required before enrollment in this study.
- •There are no known alterations in the targeted driver genes of ROS1, NTRK, BRAF, METexon 14 skipping or RET.
- •· Has not received systematic anti-tumor treatment 2) Subjects with AGA: There must be previous test results confirming the existence of one or more targeted driver gene alterations.
- •Previous failure of at least one line of standard treatment should include at least targeted therapy for driver gene alterations (patients with EGFR mutations must be treated with EGFR inhibitors).
Exclusion Criteria
- •Subjects who meet any of the following criteria will not be eligible for this study:
- •There should be a history of other malignant tumors within 3 years prior to the first medication, except for cured cervical carcinoma in situ or basal cell carcinoma of the skin.
- •There have been adverse events in the past that led to the permanent termination of immunotherapy; Or there was a history of grade ≥2 immune-related pneumonia or immune-related myocarditis;
- •Has a history of (non-infectious) interstitial lung disease (ILD), and currently still requires steroid drug treatment; Or currently having active ILD, or suspected through imaging researchers at the time of screening that there is a risk of ILD aggravation or that they are not suitable to participate in this study;
- •It is known that the subject has had a severe allergic reaction to macromolecular protein preparations/monoclonal antibodies in the past, or is allergic to the components of the test drug preparation;
- •Within two weeks before the first medication, there is an active systemic infectious disease that requires intravenous antibiotic treatment;
- •The subjects have poorly controlled clinical symptoms or diseases of the cardiovascular and cerebrovascular system, including but not limited to: (1) NYHA grade II or above heart failure or left ventricular ejection fraction (LVEF) \< 50%; (2) Unstable angina pectoris; (3) Has experienced myocardial infarction or cerebrovascular accident within 6 months (excluding lacunar infarction, mild cerebral ischemia or transient ischemic attack); (4) Poorly controlled arrhythmias (including QTc intervals of ≥ 450 ms in men and ≥ 470 ms in women) (QTc intervals are calculated using the Fridericia formula);
- •Subjects who had experienced the following diseases within 12 months prior to the first administration: a history of lower esophageal varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, abdominal abscess or a history of acute gastrointestinal bleeding; Subjects who have experienced the following diseases within 6 months prior to the first administration: any arterial thromboembolic event, NCI CTCAE V.5.0 grade 3 or higher venous thromboembolism, transient ischemic attack, cerebrovascular accident, hypertensive crisis or history of hypertensive encephalopathy, subjects with history of acute exacerbation of chronic obstructive pulmonary disease; Patients currently suffering from hypertension with a systolic blood pressure of ≥160 MMHG or a diastolic blood pressure of ≥100 MMHG after oral antihypertensive drug treatment.
- •Known to have meningeal metastasis, or uncontrolled or symptomatic central nervous system (CNS) metastasis, manifested as clinical symptoms, cerebral edema, spinal cord compression and/or progressive growth. Subjects with a history of central nervous system metastasis or spinal cord compression who have clearly received treatment and have been determined by the investigator to have stable clinical manifestations after discontinuing anticonvulsants and steroids for 8 weeks before the start of the study treatment can be enrolled in the study. Untreated, asymptomatic subjects with brain metastases (i.e., those without neurological symptoms, no need for corticosteroid hormones, no long diameter of any brain metastases \>1.5 cm, and no obvious edema around the brain metastases) can be enrolled. Brain metastases are not regarded as target lesions.
- •There is a known active or suspected autoimmune disease. However, subjects with autoimmune hypothyroidism who have received thyroid hormone replacement therapy are allowed to participate in the study; Allow controlled type 1 diabetes subjects receiving insulin treatment to participate in the study;
Arms & Interventions
Phase Ia：Dose Escalation
A total of seven dose escalations were preset: Dose1, Dose2, Dose3, Dose4, Dose5, Dose6.
Intervention: HLX37
Phase Ib：Dose Expansion
patients with advanced NSCLC;Participants will receive the RP2D identified in Dose Escalation Study .
Intervention: HLX37
Outcomes
Primary Outcomes
The Dose-Limiting Toxicity (DLT) of HLX37 within 21 days after the first Administration
Time Frame: From first dose to the end of Cycle 1 (each cycle is 3 weeks)
DLT refers to the AEs that are determined to be related to the investigational product by the investigator, whose severity will affect the escalation of dose level. In this study, the DLT observation period lasts for 21 days after the first administration of HLX37.
2. The maximum tolerated dose (MTD) of HLX37
Time Frame: From first dose to the end of Cycle 1 (each cycle is 3 weeks)
The highest dose level, at which DLT is observed in no more than one of 6 evaluable patients, is defined as MTD of HLX37
Secondary Outcomes
- Duration of response (DOR)(approximately up to 24 months.)
- Progression-free survival (PFS)(approximately up to 24 months.)
- Cmax(Up to 21 days after the first dose)
- Objective response rate (ORR)(approximately up to 24 months)
- Overall survival (OS)(approximately up to 24 months)