| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First-Line Therapy for Locally Advanced or Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| First-Line Therapy for Locally Advanced or Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the clinical efficacy of HLX10 + chemotherapy vs chemotherapy as first-line therapy in patients with locally advanced or metastatic squamous NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
To compare the safety of HLX10 + chemotherapy vs chemotherapy as first-line therapy in patients with locally advanced or metastatic squamous NSCLC.
To evaluate pharmacokinetics (PK), immunogenecity and biomarker |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Voluntary participation in the clinical study; fully aware and informed of the study and sign the Informed Consent Form (ICF); willing to comply with and able to complete all trial procedures.
2. Male or female at least 18 years old (inclusive) at the time of signing the ICF.
3. Patients with histologically or cytologically confirmed stage IIIB/IIIC or stage IV (AJCC Edition 8) squamous NSCLC where surgery or radiotherapy cannot be performed.
4. No known sensitizing EGFR mutations, ALK, ROS1 gene rearrangements.
Note: Patients with known EGFR mutations, ALK, ROS1 rearrangements will be excluded; if EGFR, ALK, ROS1 status is unknown, testing of mutations such as EGFR may be considered if there are high risk factors (e.g. non-smoking female patients).
5. Patients who have not received systemic therapy for stage IIIB/IIIC or stage IV NSCLC. For patients who have received adjuvant or neoadjuvant therapy, if adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of stage IIIB/IIIC or stage IV NSCLC, the enrollment will be permitted.
6. Previous non-systematic anti-tumor treatment should be completed ≥2 weeks prior to the initiation of study medication, and treatment related AEs have returned to ≤grade 1 based on Common Terminology Criteria for Adverse Events (CTCAE) 5.0 (except grade 2 hair loss).
7. Within 4 weeks prior to randomization, there should be at least one measurable target lesion assessed by IRRC in accordance with the requirements of RECIST 1.1.
Note: Measurable target lesions cannot be selected from sites that have been previously irradiated with the following exception. If no alternative lesion can be used as target lesion, the investigator should provide the before and after imaging data showing significant progression of the lesion after the completion of radiotherapy.
8. Patients must provide tumor tissues that meet the requirements for the determination of PD-L1 expression levels.
Note: Formalin-fixed tumor tissue samples collected within 6 months prior to the first dose of study drug is recommended. Paraffin embedded tumor specimens (preferred) or unstained fresh serial sections (adhesion slides preferred). Relevant pathological report of the aforementioned specimens must also be provided. Freshly collected specimens, resection, core needle biopsy, excision, incision, punch or forceps biopsies are within acceptable range (newly obtained tissue preferred). Samples collected by needle aspiration (i.e., samples without complete tissue structure that are only provided for cell suspension and/or cell smear), brushing samples, and precipitated cell samples that come from pleural or peritoneal effusion are not acceptable. Refer to the laboratory’s operating manual for details on the tissue sample requirements.
9. The ECOG PS score should be 0 or 1 within 7 days prior to the first dose of study drug.
10. Expected survival ≥12 weeks.
11. Major organs are functioning well - please see the relevant criteria in the protocol (have not received transfusion, albumin, recombinant human thrombopoietin or colony-stimulating factor [CSF] therapy within 14 days prior to the first dose of study drug):
12. Female patients must meet the following:
i. Menopause (defined as absence of menstrual period for at least 1 year and no other confirmed causes other than menopause), or
ii. Have undergone sterilization operation (removal of ovaries and/or uterus), or
iii. Have child-bearing potential, but must meet the following:
o Serum pregnancy test must be negative within 7 days prior to randomization, and
o Agree to use birth control methods with an annual failure rate of <1% or maintain abstinence (avoid heterosexual intercourse) (from the signing of ICF to at least 6 months after the final dose of study drug or at least 6 months after the final dose of chemotherapy drug) (birth control methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, proper use of hormonal contraceptives that inhibit ovulation, hormone releasing intrauterine contraceptive devices and copper containing intrauterine contraceptive devices or condoms), and
o Must not be breast-feeding.
13. Male patients must meet the following: Agree to abstinence (avoid heterosexual intercourse) or use barrier contraceptive measures, as specified below: Male patients with partners of child-bearing potential or pregnant partners must maintain abstinence or use condoms during chemotherapy (carboplatin or nab-paclitaxel) and for at least 6 months after the final dose of chemotherapy drug to prevent embryo exposure to the drug. Periodic abstinence (e.g., contraception methods based on calendar day, ovulation period, basal body temperature or post ovulation period) and in vitro ejaculation are not acceptable birth control methods.
14. Patients with prior denosumab use who can agree to switch to
bisphosphonate therapy for bone metastases in the study. |
|
| E.4 | Principal exclusion criteria |
1. Patients with histologically non-squamous NSCLC. Mixed tumors will be classified according to the primary cell type. Patients are not eligible if small cell components and neuroendocrine carcinoma components are present in the cancer tissue. For non-small cell histology, patients are eligible if squamous components (e.g., adenosquamous) are present.
2. Patients who have other concurrent malignancy within the past 5 years. Patients with cured localized tumors, such as basal cell carcinoma, cutaneous squamous cell carcinoma, superficial bladder cancer, prostate carcinoma in situ, cervical carcinoma in situ and ductal carcinoma in situ, are eligible.
3. Patients who are preparing to undergo or have undergone organ or hematopoietic stem cell transplantation.
4. Patients with uncontrollable pleural effusion, pericardial effusion, or ascites.
5. Patients who have known or active central nervous system (CNS) metastases and/or carcinomatous meningitis during the screening period. 6. Patients with spinal cord compression that cannot be cured by surgery and/or radiotherapy.
7. Patients with significant hemoptysis per the investigator, and concomitant superior vena cava syndrome.
8. Patients with myocardial infarction, or poorly controlled arrhythmia (including QTc interval ≥450 ms for males, ≥470 ms for females) (QTc interval is calculated using the Fridericia formula) within 6 months prior to the first dose of study drug;
9. Class III - IV cardiac insufficiency or echocardiogram in accordance with the New York Heart Association (NYHA) standards: left ventricular ejection fraction (LVEF) <50%.
10. Patients with poorly controlled hypertension (refers to systolic blood pressure [BP] ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg), and have hypertensive crisis or hypertensive encephalopathy.
11. Patients who have ≥ Grade 2 peripheral neuropathy by the CTCAE 5.0
12. Patients with human immunodeficiency virus (HIV) infection.
13. Patients with active tuberculosis.
14. Patients with past and current history of interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, and severe impairment of pulmonary function that may interfere with the detection and handling of suspected drug-related pulmonary toxicity.
15. Patients who have known active or suspected autoimmune disease. Patients with a history of autoimmune disease and do not require systemic immunosuppressive therapy for more than 12 months are eligible.
16. Patients with hepatitis B (tested positive for HBsAg or positive for HBcAb and HBV DNA) and hepatitis C (tested positive for HCV antibody and positive for HCV RNA). Subjects co-infected with hepatitis B and C (tested positive for HBsAg or HBcAb and positive for HCV antibody).
17. Patients who have received live vaccines within 28 days prior to the first dose of study drug. However, inactivated influenza vaccines are allowed. However, live attenuated influenza vaccines for intranasal use are not allowed.
18. Patients who require systemic glucocorticoids (>10 mg/day therapeutic dose of prednisone) or other immunosuppressive drugs within 14 days prior to the first dose of study drug or during the study period. However, enrollment is permitted for the following situations: In absence of active autoimmune disease, patients are allowed to use topical or inhaled glucocorticoids and ≤10 mg/day therapeutic dose of prednisone for adrenal glucocorticoid replacement therapy.
19. Any active infection requiring systemic anti-infective therapy within 14 days prior to the first dose of study drug.
20. Patients who have received major surgery within 28 days prior to the first dose of study drug. Major surgeries are defined as surgeries that require at least 3 weeks of post-surgery recovery time. Patients who have undergone tumor biopsy or incisional lymph node biopsy are eligible.
21. Patients who have received definitive radiotherapy within 3 months prior to the first dose of study drug.
22. Patients who previously received other antibodies/drugs targeted at immune checkpoints, such as PD-1, PD-L1, CTLA4 and other treatments.
23. Patients who are currently participating in other clinical studies, or have ended their participation in the previous clinical study for less than 14 days before the planned initiation of this study treatment;
24. Patients with known history of severe hypersensitivity to any monoclonal antibody.
25. Patients with known hypersensitivity to any compositions of carboplatin or nab-paclitaxel.
26. Pregnant or breast-feeding females.
27. Patients with a known history of psychotropic drug abuse or drug addiction; or a history of alcohol abuse.
28. Patients who have other factors that could lead to the early termination of this study based on the investigator’s judgment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
• Progression-free survival (PFS) (assessed by the independent radiology review committee [IRRC] based on Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As assessed by the independent radiology review committee. The final analysis will occur at approximately 2 years from FPI. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
• Overall survival (OS)
• PFS (assessed by the investigator based on RECIST 1.1)
• PFS assessed by the IRRC and the investigator based on a modified RECIST 1.1 for immune-based therapeutics (termed iRECIST)
• Objective response rate (ORR) (assessed by the IRRC and investigator based on RECIST 1.1)
• Duration of response (DOR) (assessed by the IRRC and the investigator based on RECIST 1.1)
• Quality of life assessment
Safety Endpoints
• Adverse events (AEs) (including serious adverse events [SAEs]), laboratory tests (routine blood test, blood chemistry, coagulation function, urinalysis, thyroid function, cardiac function), 12-lead electrocardiogram (12 lead ECG), vital signs, and physical examination, etc.
PK Endpoint
• Concentration of HLX10 in serum
Immunogenicity Endpoint
• HLX10 anti-drug antibody (ADA) positive rate
Biomarker Endpoint
• Relationship between PD-L1 expression, microsatellite instability (MSI), tumor mutation burden (TMB) in tumor tissue and efficacy
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS – occur around 3 years after study start
PFS – As assessed by the investigator based on RECIST 1.1 every 6 weeks (±7 days) within 48 weeks prior to the treatment period, and every 12 weeks (±7 days)
PFS - As assessed by the IRRC and the investigator after 48 weeks.
ORR – As assessed by the IRRC and investigator based on RECIST 1.1 every 6 weeks (±7 days) within 48 weeks prior to the treatment period, and every 12 weeks (±7 days) after 48 weeks.
DOR – As assessed by the IRRC and investigator based on RECIST 1.1 every 6 weeks (±7 days) within 48 weeks prior to the treatment period, and every 12 weeks (±7 days) after 48 weeks. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenecity and biomarker |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| China |
| United States |
| Poland |
| Italy |
| Georgia |
| Russian Federation |
| Turkey |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the date when all enrolled subjects
are treated at least 2 years, the last subject completes the last studyrelated
phone-call or visit, discontinues from the trial or is lost to
follow-up (i.e. the subject is unable to be contacted by the
investigator), which occurs first.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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