| Eligibility |
Inclusion Criteria:
- 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, the treatment schedule, the
planned study assessments (including participant completed diaries) and other
requirements of the study. This includes that they are able to understand and follow
study-related instructions.
- Have confirmed locally recurrent inoperable or mTNBC as defined by the most recent
American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP)
guidelines. Note, participants initially diagnosed with hormone receptor positive
and/or HER2-positive breast cancer must have histological confirmation of TNBC in a
tumor biopsy obtained from a local recurrence or distant metastasis site.
- Systemic treatment naïve locally advanced/metastatic participants are eligible
if:
- They have received no prior systemic therapy in the locally advanced
unresectable/metastatic setting including chemotherapy, immunotherapy, or
investigational agents.
- They have completed treatment for Stage I-III breast cancer, if indicated,
and =6 months has elapsed between the completion of treatment with curative
intent (e.g., date of primary breast tumor surgery or date of last adjuvant
chemotherapy administration, whichever occurred last) and first documented
local or distant disease recurrence.
- Participants who received one prior systemic therapy in the locally
advanced/metastatic setting are eligible if they have received systemic
chemotherapy or immunotherapy in the first-line setting. If immunotherapy was
given - a minimum of two doses of a programmed death 1 (PD-1)/programmed
death-ligand 1 (PD-L1) inhibitor must have been administered in the first-line
locally advanced unresectable/metastatic setting. Radiographic progression must
have been documented. Radiographic progression is defined as unequivocal
progression of existing tumor lesions or developing new tumor lesions as assessed
by the investigator.
- Have provided a tissue sample, archival or fresh, during the screening period (bone
biopsies, fine needle aspiration biopsies, and samples from pleural or peritoneal
fluid are not acceptable; participants with only one target lesion are not eligible to
provide a biopsy). The participants most recent formalin-fixed paraffin embedded tumor
sample should be provided (up to a maximum of 24 months prior to the start of the
study; unstained sections, 3-5 µm or tissue block). If an archival tumor sample is not
available, the participant must undergo a fresh biopsy, if medically feasible to be
eligible for the study.
- 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) 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. Note: Participants may not use
granulocyte colony-stimulating factor or granulocyte-macrophage
colony-stimulating factor to achieve these absolute neutrophil count levels
in the past 7 days.
- Platelet count =100 × 10^9/L.
- Hemoglobin =90 g/L or 5.6 mmol/L. Note: Criterion must be met without packed
red blood cell transfusion or without erythropoietin dependency within the
prior 2 weeks.
- 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 and to
require their male partners to use condoms, starting at Screening and continuously
until 6 months after receiving the last study treatment.
- Are men who are sexually active with a partner born female and have not had a
vasectomy who agree to use condoms and to practice a highly effective form of
contraception during the study, starting at Screening 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 study, starting at Screening and continuously until 6 months after
receiving the last dose of IMP.
- Are men who are willing to refrain from sperm donation, starting at Screening and
continuously until 6 months after receiving the last dose of IMP.
Exclusion Criteria:
- 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 histories of alcoholic abuse, psychotropic drug abuse, or illicit drug addiction.
- Have received any of the following therapies or drugs prior to the initiation of
study:
- Participants who received prior treatment with a PD(L)-1/Vascular Endothelial
Growth Factor bispecific antibody.
- Have received a systemic anticancer regimen within 4 weeks prior to the
initiation of study treatment or have received palliative radiotherapy within 7
days prior to the initiation of study treatment, or have received any other
chemotherapy, curative/palliative radiotherapy, biologic therapy (including tumor
vaccines, cytokines, or growth factors for tumor control) or any experimental
antitumor drugs within 4 weeks prior to the initiation of study treatment.
- Have received other systemic immunostimulatory agents or immunosuppressive
therapies (such as interferon-alpha [IFN-a], interleukin-2 [IL-2], or
methotrexate) within 4 weeks prior to the initiation of study treatment or are
within five half-lives of the treatment drug (whichever is longer). Exception:
Excluding 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 received systemic corticosteroids (at a dosage greater than 10 mg/day of
prednisone or an equivalent dose of other corticosteroids) within 3 weeks prior
to the initiation of study treatment.
- Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to
initiation of study treatment.
- Received broad-spectrum IV antibiotics therapy within 3 weeks prior to initiation
of study treatment.
- Use of any investigational product within five half-lives of first dose or within
4 weeks, whichever is longer, 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 brain metastases and meet the following criteria:
- Presence of metastases in the midbrain, pons, medulla oblongata, spinal cord,
meninges, or spinal membranes.
- Metastases in the cerebrum or cerebellum (as shown in imaging scans as brain
edema and/or progressive tumor growth).
- Presence of cerebral and cerebellar metastases is allowed if the following
conditions are met:
- Asymptomatic and no treatment is needed.
- Stable for more than 2 weeks after completion of radiotherapy, if received
radiotherapy before enrollment.
- The last corticosteroids or antiepileptic drug treatment was more than 3
weeks prior to the initiation of study treatment.
- Have active autoimmune disease that has required systemic treatment in the past 2
years (e.g., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)
is not considered a form of systemic treatment. Those who had a 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 5 years prior to the study treatment are not
allowed. Except for those: who had locally treatment and have been cured (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, and
papillary carcinoma of thyroid; including prostate cancer with CR within the past 3
years)
- 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 (QTcF) >480 ms.
- 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:
- Poorly controlled diabetes (fasting blood glucose =13.3 mmol/L).
- Uncontrolled hypertension (systolic blood pressure =160 mmHg and/or diastolic
blood pressure =100 mmHg) while on antihypertensive medicine.
- A history of hypertensive crisis or hypertensive encephalopathy.
- 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 hemorrhage or intraspinal hemorrhage.
- Tumor lesions invading large blood vessels and are at significant risk of
bleeding.
- Had thrombosis or embolism within 6 months prior to initiation of study
treatment.
- Had clinically significant hemoptysis or tumor hemorrhage of any cause within 1
month prior to the initiation of study treatment.
- Had anticoagulant therapy for therapeutic purposes (except low molecular weight
heparin for prophylaxis) within 14 days prior to the initiation of study
treatment.
- Received antiplatelet drugs including, but not limited to, aspirin (>100 mg/day),
clopidogrel (>75 mg/day), dipyridamole, ticlopidine, cilostazol, any herbal or
folk medicines know to be associated with increased bleeding risks, within 10
days 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.
- Have uncontrolled tumor-related pain requiring analgesic treatment not managed by a
stable analgesic regimen. For asymptomatic metastatic lesion, if its growth may cause
dysfunction or intractable pain (e.g., current epidural metastasis unrelated to spinal
cord compression), local treatment should be considered before screening, if
appropriate.
- Have a known or suspected hypersensitivity to the study treatments including any
active ingredient or excipients thereof.
- Have 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 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.
- Are subject to exclusion periods from another investigational study.
- Are vulnerable individuals, i.e., are individuals whose willingness to volunteer in a
clinical study may be unduly influenced by the expectation, whether justified or not,
of benefits associated with participation, or of a retaliatory response from senior
members of a hierarchy in case of refusal to participate.
- Participants with AEs from prior antitumor therapy that 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 or history of tuberculosis that was not successfully treated.
- Have underlying condition(s) that may increase risk of the combination treatment or
complicate the interpretation of toxicities and AEs, as judged by the investigator, or
other scenarios that the investigators consider the participant is not eligible for
the study.
- Those who are expected to require non-study antitumor drug therapy during the study.
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