| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Extensive Stage Small Cell Lung Cancer (ES-SCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Extensive Stage Small Cell Lung Cancer (ES-SCLC) |
|
| 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 | 10041068 |
| E.1.2 | Term | Small cell lung cancer extensive stage |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the clinical efficacy of HLX10 in combination with chemotherapy versus placebo in combination with chemotherapy in previously untreated patients with ES-SCLC. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the safety and tolerability of HLX10 in combination with chemotherapy versus placebo in combination with chemotherapy in previously untreated patients with ES SCLC and evaluate pharmacokinetics (PK), immunogenicity, and biomarkers.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Voluntary participation in clinical studies; fully understand, be informed about the study and have signed the ICF; willingness to follow and ability to complete all trial procedures.
2. Male or female aged ≥ 18 years at the time of signing the ICF.
3. Histologically or cytologically diagnosed with ES-SCLC (according to the Veterans Administration Lung Study Group staging system).
4. No prior systemic therapy for ES-SCLC (including systemic chemotherapy, molecular targeted therapy, biological therapy, and other investigational therapies, etc.).
5. Patients who have received chemoradiotherapy for previous limited stage SCLC must be treated with curative intent and have a treatment-free interval of at least 6 months from the last course of chemotherapy, radiotherapy, or chemoradiotherapy to the diagnosis of extensive stage SCLC.
6. At least one measurable lesion as assessed by the IRRC according to RECIST v1.1 within 4 weeks prior to randomization.
Note: Measurable lesions are not from previously irradiated sites. If the lesion at the previously irradiated site is the only selectable target lesion, a radiological assessment showing significant progression of the irradiated lesion should be provided by the investigator.
7. Patients must provide tumor tissues that meet the requirements for the determination of PD-L1 expression levels. Patients are assessed for an evaluable PD-L1 expression category (negative: TPS <1%, positive: TPS ≥1%, or not evaluable/not available) by the central laboratory for randomization.
Note: It is recommended to provide formalin-fixed tumor tissue samples, paraffin-embedded tumor specimens (preferred), formalin-fixed paraffin embedded (FFPE), tumor specimens or newly prepared unstained serial tissue sections (preferably adhesive slides) within 6 months prior to the first dose of study medication. A relevant pathology report must also be provided for the above specimens. Freshly collected specimens, radical resections, core needle biopsy, excisions, incisions, punch or clamp biopsies are acceptable (newly obtained tissues are preferred). Fine-needle aspirations (i.e., samples that lack a complete tissue structure and provide only cell suspension and/or cell smear), brush biopsies, and cell pellet samples from pleural or peritoneal effusions are unacceptable. For detailed requirements for tissue samples, see the laboratory manual.
8. Prior antineoplastic therapy must have been ≥ 2 weeks from the first dose in this study with treatment-related AEs resolved to NCI-CTCAE Grade ≤ 1 (except for Grade 2 alopecia).
9. An ECOG PS score of 0 or 1
10. An expected survival ≥ 12 weeks
11. Subjects with prior denosumab use that can and agree to switch to bisphosphonate therapy for bone metastases starting prior to randomization and throughout treatment.
12. Normal major organ functions as defined by the criteria listed in the protocol (no blood transfusions, or treatment with albumin, recombinant human thrombopoietin or colony-stimulating factor within 14 days prior to the first dose in this study).
13. Female patients must meet one of the following conditions:
a. Menopause (defined as no menses for at least 1 year and no confirmed cause other than menopause), or
b. Surgically sterilized (removal of the ovaries and/or uterus), or
c. With child-bearing potential, but must meet the following:
- Serum pregnancy test must be negative within 7 days prior to randomization, and
- 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) (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
- Must not be breast-feeding.
14. Male patients must: agree to abstinence (avoid heterosexual intercourse) or take contraception measures as follows: male patients with a pregnant partner or a partner with childbearing potential must remain abstinent or use a condom to prevent embryonic exposure during study treatment and for at least 6 months after the last dose of study drug. Periodic abstinence (e.g., contraceptive methods based on calendar day, ovulation, basal body temperature or post-ovulation) and external ejaculation are ineligible methods of contraception. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Histologically or cytologically confirmed mixed SCLC.
2. Other active malignancies within 5 years or at the same time. Localized tumors that have been cured, such as basal cell carcinoma, squamous-cell skin cancer, superficial bladder cancer, prostate carcinoma in situ, cervical cancer in situ and breast cancer in situ are acceptable.
3. Patients who are preparing for or have received an organ or bone marrow transplant.
4. Pleural or pericardial effusion requiring clinical intervention, or ascites.
5. Patients with known or documented active CNS metastases and/or carcinomatous meningitis at screening. However, the following subjects are allowed to be enrolled: 1) Subjects with asymptomatic brain metastases (i.e., no progressive central nervous system symptoms caused by brain metastases, no requirement for corticosteroids, and lesion size ≤ 1.5 cm) may be included, but are required to receive regular brain imaging as a site of lesion. 2) Subjects with treated brain metastases which have been stable for at least 2 months (as confirmed by 2 radiological examinations at least 4 weeks apart after treatment of brain metastases), with no evidence of new or enlarging brain metastases, and with discontinued steroids 3 days prior to study drug administration. (Stable brain metastases here should be confirmed before the first dose of the study drug.).
6. Subjects with spinal cord compression that has not been radically treated with surgery and/or radiotherapy.
7. Patients with myocardial infarction within half a year before the first dose of the study drug, poorly controlled arrhythmia (including QTc intervals ≥ 450 ms for males and ≥ 470 ms for females) (QTc intervals are calculated by Fridericia's formula).
8. Class III to IV cardiac insufficiency according to NYHA classification or a left ventricular ejection fraction < 50% by cardiac color Doppler.
9. Subject has uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN).
10. Subject with peripheral neuropathy ≥ Grade 2 by CTCAE.
11. Human immunodeficiency virus (HIV) infection, positive test for HIV antibody.
12. Active or latent pulmonary tuberculosis.
13. Subjects with previous and concurrent interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis and severe impaired pulmonary function that may interfere with the detection and management of suspected drug-related pulmonary toxicity as judged by the investigator.
14. Hepatitis B (positive test for HBsAg or HBcAb and positive test for HBV-DNA) or Hepatitis C (positive tests for HCV antibody and HCV-RNA). Hepatitis B and C co-infection (positive test for HBsAg or HBcAb and positive test for HCV antibody).
15. Known active or suspected autoimmune diseases. Subjects in a stable state with no need for systemic immunosuppressant therapy are allowed to enroll.
16. Treatment with live vaccines and all COVID-19 vaccines (fully
administered to the required number of doses) within 28 days prior to study drug administration; inactivated viral vaccines for seasonal influenza are allowed.
17. Subjects requiring treatment with systemic corticosteroids (> 10 mg/day prednisone efficacy dose) or other immunosuppressive drugs within 14 days prior to the first dose or during the study. However, in the absence of active autoimmune disease, subjects are allowed to use topical or inhaled steroids and adrenal hormone replacement therapy at doses equivalent to ≤ 10 mg/day of prednisone efficacy.
18. Any active infection requiring systemic anti-infective therapy within 14 days prior to study drug administration or subjects with a positive RT-PCR test for SARS-CoV-2 infection at randomization. Subjects with a history of COVID-19 infection must have a negative RT-PCR test prior to the first dose of the study drug.
19. Major surgery within 28 days prior to the first dose of the study drug, defined as: surgeries requiring at least 3 weeks of recovery to be able to receive treatment in this study.
20. Radical radiation therapy within 3 months prior to study medications.
21. The subject has previously received other antibodies/drugs against immune checkpoints, such as PD-1, PD-L1, CTLA4, etc.
22. Participation in any other ongoing clinical studies, or less than 14 days from the end of the previous clinical study treatment to the start of this trial.
23. Known history of severe allergy to any monoclonal antibody.
24. Known hypersensitivity to carboplatin or etoposide.
25. Pregnant or lactating women.
26. Known history of psychotropics abuse or drug abuse.
27. In the judgment of the investigator, the subject has any other factors that may lead to a premature discontinuation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
• Overall survival (OS)
|
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
• Progression-free survival (PFS) (assessed by the independent radiology review committee [IRRC] based on Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
• PFS (assessed by the investigator based on RECIST 1.1 and a modified RECIST 1.1 for immune-based therapeutics [termed iRECIST])
• PFS2 (assessed by the investigator based on RECIST 1.1)
• 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)
Safety Endpoints
• Adverse events (AEs) (including serious adverse events [SAEs]), laboratory tests (routine blood test, blood chemistry, coagulation function, urinalysis, myocardial function and thyroid function), 12-lead electrocardiogram (12 lead ECG), vital signs, and physical examination, etc.
Pharmacokinetic (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.
Quality of life assessment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
∙ OS – occur around 3.5 years after FPI
∙ PFS – As assessed by the investigator based on RECIST 1.1, at screening (within 4 weeks pre-dose), every 6 weeks (± 7 days) during the first 48 weeks after the start of study treatment, and every 9 weeks (± 7 days) after week 48.
∙ ORR – As assessed by the IRRC and investigator based on RECIST 1.1
∙ DOR – As assessed by the IRRC and investigator based on RECIST 1.1
∙ AEs - As assessed by the investigator during visit or informed by subject
PK and ADA - Sample will be collected at the following time points: within 7 days pre-dose in Cycle 1, within 3 days pre-dose in Cycles 2, 4, 6, 8 and every 4 cycles thereafter, within 2 hours after the end of dosing in Cycles 1 and 8 of treatment period (for PK only), at EOT visit and safety follow-up. |
|
| 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 | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Ukraine |
| China |
| Georgia |
| Russian Federation |
| United States |
| Poland |
| Türkiye |
|
| 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 final analysis of OS will be performed when a target number of OS events (approximately 342) are observed, and for final analysis the α is 0.046 (two-sided) based on the
O'Brien-Fleming alpha spending function.
Or
The end of the study is defined as the date when all subjects enrolled
completed the safety follow-up 90 days after the end of treatment visit.
Whichever occurs last
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 30 |
| 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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