A Phase I Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Characteristics of HLX43 (Anti-PD-L1 ADC) in Patients With Advanced/Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- HLX43
- Conditions
- Not specified
- Sponsor
- Shanghai Henlius Biotech
- Enrollment
- 340
- Locations
- 2
- Primary Endpoint
- The Dose-Limiting Toxicity (DLT) of HLX43 within 21 days after the first Administration
- Status
- Recruiting
- Last Updated
- 4 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 HLX43 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 HLX43 with escalated doses in the treatment of patients with advanced/metastatic solid tumors. In the phase Ia of this study, a 3 + 3 dose escalation method will be adopted, and the patients will be administered with HLX43 at different doses via intravenous infusion. The DLT observation period lasts for 3 weeks after the first administration of HLX43. 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. The dose expansion part will include 4 cohorts: advanced/metastatic non-small cell lung cancer (NSCLC) patients with prior failed standard treatment or no standard treatment available, advanced/metastatic thymic carcinoma (TC) patients with prior failed first line platinum based standard treatment, advanced/metastatic NSCLC patients with prior failed standard treatment and docetaxel treatment, and stage IIIB, IIIC, or IV NSCLC patients who have not received any prior treatment with positive PD-L1 expression and no EGFR sensitizing mutation or ALK/ROS gene rearrangement.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have a full understanding of the study content, process, and possible adverse reactions before the study, and sign the informed consent form (ICF); voluntarily participate in the study; be able to complete the study as per protocol requirements;
- •≥ 18 years and ≤ 75 years at the time of signing the ICF, male or female;
- •In phase Ia, enroll patients with histologically or cytologically confirmed advanced/metastatic malignant solid tumors, who are refractory to standard treatment, or for which no standard treatment is available; In phase Ib Cohort 1: enroll patients with histologically or cytologically confirmed advanced/metastatic NSCLC, who are refractory to standard treatment, or for which no standard treatment is available (The standard treatment for squamous NSCLC is defined as platinum-containing chemotherapy combined with immune checkpoint inhibitor \[ICI\]. The standard treatment for non-squamous NSCLC with known EGFR mutations is defined as EGFR inhibitors and platinum-containing chemotherapy. The standard treatment for patients with non-squamous NSCLC without EGFR mutations is defined as platinum-containing chemotherapy combined with immune checkpoint inhibitor \[ICI\] therapy); Cohort 2: enroll patients with histologically or cytologically confirmed advanced/metastatic TC, who are refractory to first line platinum based standard treatment; Cohort 3: enroll patients with histologically or cytologically confirmed advanced/metastatic NSCLC, who are refractory to standard treatment and docetaxel treatment (The standard treatment for squamous NSCLC is defined as platinum-containing chemotherapy combined with immune checkpoint inhibitor \[ICI\]. The standard treatment for non-squamous NSCLC with known EGFR mutations is defined as EGFR inhibitors and platinum-containing chemotherapy. The standard treatment for patients with non-squamous NSCLC without EGFR mutations is defined as platinum-containing chemotherapy combined with immune checkpoint inhibitor \[ICI\] therapy); Cohort 4: enroll patients with histologically or cytologically confirmed stage IIIB, IIIC, or IV NSCLC that cannot be treated with surgery or radiotherapy; positive PD-L1 expression (PD-L1 positive is defined as TPS ≥ 1%; PD-L1 expression is subject to the central laboratory result) and no EGFR sensitizing mutation or ALK/ROS gene rearrangement; no previous systemic anti-tumor therapy for NSCLC (Patients who have received adjuvant or neoadjuvant therapy are allowed to be enrolled if the adjuvant/neoadjuvant therapy has been completed at least 6 months before the diagnosis of stage IIIB, IIIC, or IV NSCLC);
- •At least one measurable lesion as per RECIST 1.1 within 4 weeks prior to the first administration;
- •An ECOG performance status score of 0-1 within 7 days prior to the first administration;
- •Life expectancy \> 3 months;
- •The following conditions must be met in terms of the time of the first administration of the investigational product: at least 28 days from the previous major surgery, medical device treatment, locoregional radiotherapy (except for palliative radiotherapy for bone lesions), cytotoxic chemotherapy, immunotherapy, or biological product therapy; at least 14 days from the previous small molecule targeted drug therapy and previous hormone therapy; at least 7 days from the administration of the traditional Chinese medicine for anti-tumor indications, or minor surgery; and recovery of treatment-induced AEs to grade ≤ 1 (CTCAE v5.0, except for alopecia);
- •Subjects who agree to provide archived tumor tissue specimens that meet the testing requirements (either from the most recent surgery or biopsy, preferably within 2 years) or agree to undergo a biopsy to collect tumor tissue for PD-L1 expression testing; Note: Formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin blocks or unstained sections, which must meet the quality control criteria for testing) collected from sites not receiving radiotherapy during the most recent surgery or biopsy at or after the diagnosis of malignant tumor and pathological reports of such specimens shall also be provided.
- •Adequate organ functions as confirmed by laboratory tests within 7 days prior to the first administration of the investigational product (no blood transfusions or treatment with granulocyte colony-stimulating factor within 14 days prior to the first administration).
- •For patients with hepatocellular carcinoma, Child-Pugh score must be A;
Exclusion Criteria
- •Subjects who meet any of the following criteria are not allowed to be enrolled:
- •Patients who have history of other malignant tumors within 2 years prior to the first administration, except for cured cervical carcinoma in situ or cutaneous basal cell carcinoma;
- •Patients who previously have immune-related adverse events (irAEs) ≥ grade 3 in immunotherapy;
- •Patients who have history of (non-infectious) interstitial lung disease (ILD) requiring steroids, or current ILD, or suspected ILD that cannot be ruled out by imaging at screening;
- •Subjects who are known to have anaphylaxis to protein preparations/monoclonal antibodies or are allergic to any component in the formulation of the investigational product;
- •Patients who have active systemic infectious diseases requiring intravenous antibiotics within 2 weeks prior to the first administration of the investigational product;
- •Subjects who have any poorly-controlled cardiovascular and cerebrovascular clinical symptoms or diseases, including but not limited to: (1) NYHA Class II or greater heart failure or left ventricular ejection fraction (LVEF) \< 50%; (2) unstable angina pectoris; (3) myocardial infarction or cerebrovascular accident within 6 months (except for lacunar infarction, slight cerebral ischemia, or transient ischemic attack); (4) poorly controlled arrhythmia (including QTc intervals ≥ 450 ms for males and ≥ 470 ms for females) (QTc intervals are calculated by Fridericia's formula); (5) poorly-controlled hypertension (systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg after active treatment);
- •Patients who have been assessed as unsuitable for inclusion by the investigator, due to brain metastases, spinal cord compression, or cancerous meningitis with clinical symptoms, or uncontrolled brain or spinal cord metastases that have been evidenced; Note: Patients with asymptomatic or stable brain metastases, spinal cord compression, or cancerous meningitis as judged by the investigator are allowed to be enrolled;
- •Patients with known active or suspected autoimmune diseases. Those with autoimmune-related hypothyroidism and receiving thyroid hormone replacement therapy and those with type 1 diabetes mellitus controlled with insulin therapy are eligible to be enrolled;
- •Patients who have received systemic corticosteroids (prednisone \> 10 mg/day or an equivalent dose of a similar drug) or other immunosuppressive agents within 14 days prior to the first administration; Except for the following circumstances: patients treated with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids; those with short-term use of corticosteroids for prophylaxis if a contrast agent is used;
Arms & Interventions
Ia (Dose Escalation)
Patients with advanced/metastatic solid tumors
Intervention: HLX43
NSCLC failed to standard treatment (Part 2 Dose Expansion)
Patients with advanced/metastatic NSCLC, who are refractory to standard treatment, or for which no standard treatment is available.
Intervention: HLX43
Thymic carcinoma (Part 2 Dose Expansion)
Patients with advanced/metastatic Thymic carcinoma, who are refractory to first line platinum based standard treatment.
Intervention: HLX43
NSCLC failed to standard and docetaxel treatment (Part 2 Dose Expansion)
Patients with advanced/metastatic NSCLC, who are refractory to standard treatment and docetaxel.
Intervention: HLX43
Stage IIIB, IIIC, or IV NSCLC without any prior treatment (Part 2 Dose Expansion)
Patients with stage IIIB, IIIC, or IV NSCLC that cannot be treated with surgery or radiotherapy, positive PD-L1 expression and no EGFR sensitizing mutation or ALK/ROS gene rearrangement, no previous systemic anti-tumor therapy for NSCLC.
Intervention: HLX43
Stage IIIB, IIIC, or IV NSCLC without any prior treatment (Part 2 Dose Expansion)
Patients with stage IIIB, IIIC, or IV NSCLC that cannot be treated with surgery or radiotherapy, positive PD-L1 expression and no EGFR sensitizing mutation or ALK/ROS gene rearrangement, no previous systemic anti-tumor therapy for NSCLC.
Intervention: HLX10
Outcomes
Primary Outcomes
The Dose-Limiting Toxicity (DLT) of HLX43 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 HLX43.
Objective response rate (ORR)
Time Frame: approximately up to 24 months
Percentage of participants with complete response (CR) and partial response (PR) based on investigator assessment.
The maximum tolerated dose (MTD) of HLX43
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 HLX43
RP2D
Time Frame: approximately up to 24 months
The recommended phase 2 dose of HLX43
Secondary Outcomes
- Duration of response (DOR)(approximately up to 24 months.)
- Progression-free survival (PFS)(approximately up to 24 months)
- Overall survival (OS)(approximately up to 24 months)
- Cmax(Up to 21 days after the first dose)
- Tmax(Up to 21 days after the first dose)
- T1/2(Up to 21 days after the first dose)
- ADA (anti-drug antibody)(approximately up to 24 months)
- Nab (neutralizing antibody)(approximately up to 24 months)
- Number of subjects experiencing adverse events(Day 1 through 90 days after last dose.)