| Eligibility |
Inclusion Criteria (applicable to all participants unless otherwise specified):
- Cohort 1 only: Have histologically or cytologically confirmed ES-SCLC (using the
American Joint Committee on Cancer [AJCC]) tumor node metastasis [TNM] staging system
combined with Veterans Administration Lung Study Group two-stage classification
scheme). For AJCC TNM staging system: AJCC 8th edition stage IV (T any, N any,
M1a/b/c), or T3~4 for multiple lung nodules or tumor/nodule volume that cannot be
encompassed in a tolerable radiotherapy plan.
- Cohort 1 only: Participants without prior systemic therapy for ES-SCLC. However,
participants with prior chemoradiotherapy for Limited-Stage Small-Cell Lung Cancer
(LS-SCLC) must have been treated with curative intent and had a treatment-free
interval of at least 6 months since the last systemic anticancer treatment including
chemotherapy, radiotherapy, or chemoradiotherapy before the diagnosis of ES-SCLC to be
eligible.
- Cohort 2 and Cohort 3 only: Participants with SCLC who have disease
progression/relapse after first-line platinum-based chemotherapy with or without
immunotherapy, or after first-line platinum-based chemotherapy and one second-line of
chemotherapy (not the same chemotherapy agent in the specific arm to be enrolled to)
with time to progression (TTP) =3 months during second-line treatment.
- Have given informed consent by signing and dating the informed consent form before
initiation of any study-specific procedures.
- Male or female, aged =18 years at the time of giving informed consent.
- Are willing and able to comply with scheduled visits, treatment schedule, the planned
study assessments, laboratory tests, lifestyle restrictions, and other requirements of
the study. This includes that they are able to understand and follow study-related
instructions.
- Have at least one measurable lesion as the targeted lesion based on RECIST 1.1.
Lesions treated after prior local treatment (radiotherapy, ablation, interventional
procedures, etc.) are generally not considered as target lesions. If the lesion with
prior local treatment is the only targeted lesion, evidence-based radiology must be
provided to demonstrate disease progression (the single bone metastasis or the single
central nervous system metastasis should not be considered as a measurable lesion).
- Eastern Cooperative Oncology Group performance status of 0 or 1.
- Have a minimum life expectancy of >3 months.
- Have adequate organ function, as defined below:
- Hematology:
- Absolute neutrophil count =1.5 × 10^9/L.
- Platelet count =100 × 10^9/L.
- Hemoglobin =90 g/L or 5.6 mmol/L.
- Liver function:
- Total bilirubin =1.5 × upper limit of normal (ULN).
- With Gilbert's syndrome total bilirubin <3 mg/dL and direct bilirubin =ULN.
Note, Gilbert's syndrome must be documented appropriately as past medical
history.
- Participants without liver metastasis alanine aminotransferase and aspartate
aminotransferase =2 × ULN.
- Participants with liver metastasis alanine aminotransferase and aspartate
aminotransferase =5 × ULN.
- Albumin =3.0 g/dL.
- Renal function: Serum creatinine =1.5 × ULN or creatinine clearance =50 mL/min.
Cockcroft-Gault formula.
- Qualitative urine protein =1+. If qualitative urine protein =2+, a 24-hour urine
protein quantitative test is required. If the 24-hour urine protein result is <1
g, the participant can be enrolled.
- Coagulation function: International normalized ratio or prothrombin time and
activated partial thromboplastin time =1.5 × ULN unless the participant is
receiving anticoagulation therapy as long as prothrombin or activated partial
thromboplastin is within therapeutic range of intended use of anticoagulant.
- Are women of childbearing potential (WOCBP) who have a negative serum beta-human
chorionic gonadotropin test at screening and before each IMP dose. Women born female
that are postmenopausal (defined as 12 months with no menses without an alternative
medical cause) or permanently sterilized (verified by medical records) will not be
considered WOCBP and therefore will not be required to undergo pregnancy testing.
- Are WOCBP who agree to practice a highly effective form of contraception during the
Screening Period and continuously until 6 months after receiving the last dose of IMP.
- Are men who are sexually active with a partner born female and have not had a
vasectomy who agree to use condoms and to ask their sexual partners to practice a
highly effective form of contraception during the study, starting at the Screening
Period and continuously until 6 months after receiving the last dose of IMP.
- Are WOCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study, starting at the Screening Period and continuously 6
months after receiving the last dose of IMP.
- Are men who are willing to refrain from sperm donation, starting at the Screening
Period and continuously until 6 months after the last dose of IMP.
Exclusion Criteria (applicable to all participants):
- Are pregnant or breastfeeding or are planning pregnancy or planning to father children
during the study or within 60 days or five half-lives if known (whichever is longer)
after the last dose of IMP.
- Have a medical, psychological, or social condition which, in the opinion of the
investigator, could compromise their wellbeing if they participate in the study, or
that could prevent, limit, or confound the protocol-specified assessments or
procedures, or that could impact adherence to protocol-described requirements.
- Have histologically or cytologically confirmed SCLC with combined histologies.
- Have received any of the following therapies or drugs within the noted time intervals
prior to the initiation of study treatment:
- Within 2 weeks: small molecule targeted agents with half-life of <7 days; or
radiation not involving the thoracic cavity; local radiation for brain lesion is
allowed; local radiation for bone lesions is allowed.
- Within 4 weeks: radiation involving the thoracic cavity; small molecule targeted
agents with half-life of =7 days; monoclonal antibodies, antibody-drug
conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies.
- Participants who received prior treatment with a PDL-1/VEGF bispecific antibody.
- Have received systemic corticosteroids (at a dosage greater than 10 mg/day of
prednisone or an equivalent dose of other corticosteroids) within 10 days prior
to the initiation of study treatment. Note: The following are allowed: local,
intranasal, intraocular, intra-articular or inhaled corticosteroids, short-term
use (=7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast
agent allergy) or treatment of non-autoimmune conditions (e.g., delayed
hypersensitivity reactions caused by exposure to allergens).
- Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to
initiation of the study treatment.
- Received broad-spectrum intravenous antibiotics therapy within 2 weeks prior to
initiation of study treatment.
- Use of any non-study IMP within 3 weeks before initiation of study treatment in
this study or ongoing participation in the active treatment phase of another
interventional clinical study.
- Have undergone major organ surgery (core needle biopsies are allowed >7 days prior
study start), significant trauma, or invasive dental procedures (such as dental
implants) within 28 days prior to the initiation of study treatment or plan to undergo
elective surgery during the study. Placement of vascular infusion devices is allowed.
- Have received allogeneic hematopoietic stem cell transplantation or organ
transplantation.
- Have the following central nervous system metastases:
- Participants with untreated brain metastases that are symptomatic or large (e.g.,
>2 cm).
- Participants who received treatment for central nervous system metastases are not
neurologically stable or still on steroids 10 days before initiating IMP of this
study.
- Participants with known leptomeningeal metastases.
- Have active autoimmune disease or history of autoimmune diseases with anticipated
relapse (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis,
etc.), except for those with clinically stable autoimmune thyroid disease or type 1
diabetes.
- Have had other malignant tumors within 2 years prior to the study treatment are not
allowed. Except for those: who have been cured with local treatment (such as basal
cell or squamous cell carcinoma of the skin, superficial or non-invasive bladder
cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast,
papillary carcinoma of thyroid and early stage prostate cancer).
- Have any of the following heart conditions within 6 months prior to the study
treatment:
- Acute coronary syndrome, coronary artery bypass grafting, congestive heart
failure, aortic dissection, stroke, or other Grade 3 and above cardiovascular and
cerebrovascular events.
- New York Heart Association functional classification =II heart failure or left
ventricular ejection fraction <50%.
- Those who have ventricular arrhythmias requiring clinical intervention, second-
to third-degree atrioventricular block, or congenital long QT syndrome.
Participants with treated cardiac arrythmia/atrial fibrillation are allowed.
- Mean QT interval corrected by Fridericia's method >480 ms (the electrocardiogram
can be repeated at the discretion of the investigator).
- Use of cardiac pacemaker.
- Cardiac troponin I or N >2 x ULN.
- Have any of the following hypertension or diabetic conditions prior to initiation of
study treatment:
- Uncontrolled hypertension (systolic blood pressure =160 mmHg and/or diastolic
blood pressure =100 mmHg) while on antihypertensive medicine.
- Those with a history of hypertensive crisis or hypertensive encephalopathy.
- Poorly controlled diabetes (fasting blood glucose =13.3 mmol/L [240 mg/dL]).
- Have serious non-healing wounds, ulcers, or bone fractures. This includes history of
abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess for which
an interval of 6 months must pass before enrollment into this study. In addition, the
participant must have undergone correction (or spontaneous healing) of the
perforation/fistula and/or the underlying process causing the fistula/perforation.
- Participants with evidence of major coagulation disorders or other significant risks
of hemorrhage such as:
- History of intracranial or intraspinal hemorrhage.
- Tumor lesions invading large vessels and with significant risk of bleeding
- Had clinically significant hemoptysis or tumor hemorrhage within 1 month prior to
the initiation of study treatment.
- Have uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures (once monthly or more frequently). Participants with
indwelling catheters (e.g., PleurX) are allowed. However, participants who are
clinically stable following treatment for these conditions (including therapeutic
thoraco- or paracentesis or with indwelling catheters, e.g., PleurX) are allowed.
- Participants with a history of serious Grade 3 or higher immune-related adverse events
(irAEs) that led to treatment discontinuation of a prior immunotherapy. Participants
with a history of Grade 3 or higher irAEs that did not lead to treatment
discontinuation of a prior immunotherapy should be discussed with the sponsor.
- Have a known or suspected hypersensitivity to the study treatments including any
active ingredient or excipients thereof.
- Have known human immunodeficiency virus infection or known acquired immunodeficiency
syndrome, with the following exceptions:
- Participants with cluster of differentiation 4 (CD4)+ T-cell (CD4+) counts =350
cells/µL per local laboratory should generally be eligible for the study.
- Participants who have not had an opportunistic infection within the past 12
months.
- Have a known history/positive serology for hepatitis B requiring active antiviral
therapy (unless immune due to vaccination or resolved natural infection or unless
passive immunization due to immunoglobulin therapy). Individuals with positive
serology must have hepatitis B virus viral load below the limit of quantification.
- Have an active hepatitis C virus infection; individuals who have completed curative
antiviral treatment with hepatitis C virus viral load below the limit of
quantification are allowed.
- Participants with AEs from prior antitumor therapy whose AE(s) have not returned to
Grade 1 (graded by CTCAE v5.0 criteria) or below (unless the investigator determines
that certain AEs pose no safety risk to participants, such as hair loss, Grade 2
peripheral neuropathy or stable hypothyroidism under hormone replacement therapy) are
not eligible for the study.
- Have superior vena cava syndrome or symptoms of spinal cord compression.
- Those with active, or a history of, pneumonitis requiring treatment with steroids, or
has active, or a history of, interstitial lung disease. Those with a history of
pulmonary fibrosis, or currently diagnosed with severe lung diseases such as
interstitial pneumonia, pneumoconiosis, chemical pneumonitis, or any other condition
resulting in significant impairment in lung function. Exception: Asymptomatic
interstitial changes caused by previous radiation therapy, chemotherapy, or other
factors such as smoking are acceptable.
- Have active tuberculosis.
- Have underlying condition(s) that may increase the risk of the combination treatment
or complicate the interpretation of AEs, as judged by the investigator, or other
scenarios in which the investigator consider the participant as not eligible for the
study.
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