|
|
Female patients ≥19 years old |
|
|
|
|
|
Histologically proven metastatic triple-negative breast cancer irrespective of PD-L1 status |
|
|
|
|
|
Histological or cytological diagnosis of relapsed/metastatic triple receptor negative breast cancer (TNBC).TNBC is defined negatively expression of estrogen(ER), progesterone(PR) and human epidermal receptor-2(HER2). If there is a pathology report of the metastasis, take the histopathology of the metastases as standard. Negative of ER and PR is defined as expression of ER, PR<1% of the tumor cells by immunohistochemistry (IHC). HER2-negative is defined as a score of 0 and 1+ by IHC, or IHC 2+ & fluorescent in situ hybridization (FISH) negative. If the ER2 test result is 0 or 1+ by IHC, FISH detection is optional, but the result must be negative |
|
|
|
|
|
Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue |
|
|
|
|
|
Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut |
|
|
|
|
|
Has measurable disease per RECIST 1.1 as assessed by the local site |
|
|
|
|
|
investigator/radiology. Lesions situated in a previously irradiated area are |
|
|
|
|
|
considered measurable if progression has been demonstrated in such lesions |
|
|
|
|
|
Has received one or two prior lines of systemic therapy for metastatic or inoperable locally advanced TNBC |
|
|
|
|
|
No previous therapy with anti-VEGF, anti-VEGFR or anti-PD-1 antibody for their metastatic disease. The use of anti-VEGF, anti-VEGFR, anti-PD-1 or anti-PD-L1 antibody in neoadjuvant or adjuvant setting will be allowed if there was no progression of disease within 6 months after the completion of treatment |
|
|
|
|
|
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 |
|
|
|
|
|
Adequate hematologic, renal, and hepatic function tests performed within 7 days prior to initiation of study treatment |
|
|
|
|
|
Hematologic tests |
|
|
|
|
|
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L |
|
|
|
|
|
Platelets ≥ 100 x 109/L |
|
|
|
|
|
Haemoglobin ≥ 9.0 g/dL (This must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin, e.g. ≥ approximately 3 months) |
|
|
|
|
|
Blood coagulation tests |
|
|
|
|
|
Prothrombin time (PT) ≤ 1.5 x Upper limit of normal (UNL) |
|
|
|
|
|
Activated partial thromboplastin time (aPTT) ≤ 1.5 x UNL |
|
|
|
|
|
Hepatic function tests |
|
|
|
|
|
Total bilirubin ≤ 1.5 x UNL |
|
|
|
|
|
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastasis) |
|
|
|
|
|
Renal function test - Creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥30 mL/min |
|
|
|
|
|
for patient with creatinine levels >1.5 × institutional ULN 9) HIV infected |
|
|
|
|
|
participants must be on anti-retroviral therapy (ART) and have a well- |
|
|
|
|
|
controlled HIV infection/disease defined as |
|
|
|
|
|
Participants on ART must have a CD4+ T-cell count 350 cells/mm3 at time of screening |
|
|
|
|
|
Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening |
|
|
|
|
|
Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1) 10) Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization |
|
|
|
|
|
Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention |
|
|
|
|
|
Hepatitis B screening tests are not required unless |
|
|
|
|
|
• Known history of HBV infection |
|
|
|
|
|
• As mandated by local health authority 11) Participants with history of HCV |
|
|
|
|
|
infection are eligible if HCV viral load is undetectable at screening |
|
|
|
|
|
Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization |
|
|
|
|
|
Hepatitis C screening tests are not required unless |
|
|
|
|
|
• Known history of HCV infection |
|
|
|
|
|
• As mandated by local health authority 12) The patient should provide written |
|
|
|
|
|
informed consent |
|
|
|
|
|
A patient who meets any of the following criteria is excluded from participating in this
|
|
|
|
|
|
study
|
|
|
|
|
|
Is currently participating in or has participated in a study of an investigational
|
|
|
|
|
|
agent or has used an investigational device within 4 weeks prior to the first dose of
|
|
|
|
|
|
study treatment
|
|
|
|
|
|
Note: Participants who have entered the follow-up phase of an investigational study
|
|
|
|
|
|
may participate as long as it has been 4 weeks after the last dose of the previous
|
|
|
|
|
|
investigational agent
|
|
|
|
|
|
Has known active CNS metastases and/or carcinomatous meningitis. Participants with
|
|
|
|
|
|
previously treated brain metastases may participate provided they are radiologically
|
|
|
|
|
|
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
|
|
|
|
|
|
(note that the repeat imaging should be performed during study screening), clinically
|
|
|
|
|
|
stable and without requirement of steroid treatment for at least 14 days prior to
|
|
|
|
|
|
first dose of study treatment
|
|
|
|
|
|
Treatment with systemic chemotherapy, hormonal therapy, immunotherapy or biologic
|
|
|
|
|
|
therapy within 4 weeks prior to the baseline visit
|
|
|
|
|
|
Has received prior radiotherapy within 2 weeks of start of study treatment. Patients
|
|
|
|
|
|
must have recovered from all radiation-related toxicities, not require
|
|
|
|
|
|
corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted
|
|
|
|
|
|
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
|
|
|
|
|
|
Not recovered below National Cancer Institute -Common Terminology Criteria for Adverse
|
|
|
|
|
|
events (NCI-CTCAE v5.0) grade 1 or baseline from AEs due to previous therapy (patient
|
|
|
|
|
|
with ≤ Grade 2 neuropathy or alopecia may be eligible)
|
|
|
|
|
|
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
|
|
|
|
|
|
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
|
|
|
|
|
|
immunosuppressive therapy within 7 days prior the first dose of study drug
|
|
|
|
|
|
Has an active autoimmune disease that has required systemic treatment in past 2 years
|
|
|
|
|
|
(i.e., 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 and is allowed
|
|
|
|
|
|
Has a known additional malignancy that is progressing or has required active treatment
|
|
|
|
|
|
within the past 2 years. (Note: Patients with basal cell carcinoma of the skin
|
|
|
|
|
|
squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma
|
|
|
|
|
|
cervical cancer in situ) controlled by curative therapy are not excluded)
|
|
|
|
|
|
Has a history of (non-infectious) pneumonitis/interstitial lung diseases that required
|
|
|
|
|
|
steroids or current pneumonitis/interstitial lung disease
|
|
|
|
|
|
Has an active infection requiring systemic antibiotics
|
|
|
|
|
|
HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric
|
|
|
|
|
|
Castleman Disease
|
|
|
|
|
|
Active psychiatric disorder (schizophrenia, major depressive disorder, bipolar
|
|
|
|
|
|
disorder etc.) or substance abuse disorder that would interfere with the participant's
|
|
|
|
|
|
ability to cooperate with the requirements of the study. Treated depression with
|
|
|
|
|
|
ongoing antidepressant medication is not an exclusion criterion
|
|
|
|
|
|
Female who is pregnant or lactating and of childbearing potential who does not agree
|
|
|
|
|
|
to a reliable and adequate method of contraceptiona A women of childbearing potential
|
|
|
|
|
|
(WOCBP) must agree to use contraception during the treatment period and for at least 6
|
|
|
|
|
|
months (for females) after the last dose of study treatment
|
|
|
|
|
|
aAdequate contraception allowed in this trial is as follows - Hormonal contraceptives
|
|
|
|
|
|
such as combined oral contraceptive pill - Intrauterine devices or the implantation of
|
|
|
|
|
|
intrauterine system (IUD)
|
|
|
|
|
|
Blockage methods (spermicides and condoms/spermicides and [vaginal] diaphragm for
|
|
|
|
|
|
contraception, vaginal sponges or cervical cap)
|
|
|
|
|
|
Sterilization surgery such as tubal ligation in females A WOCBP who has a
|
|
|
|
|
|
positive urine pregnancy test (within 72 hours) prior to treatment. If the urine
|
|
|
|
|
|
test is positive or cannot be confirmed as negative, a serum pregnancy test will
|
|
|
|
|
|
be required
|
|
|
|
|
|
Uncontrolled hypertension (systolic blood pressure [SBP]> 150 or diastolic blood
|
|
|
|
|
|
pressure [DBP]> 90 mmHg) or seizure
|
|
|
|
|
|
Class III or IV heart failure by New York Heart Association (NYHA) classification
|
|
|
|
|
|
Requiring therapeutic anticoagulation treatment (prophylactic therapy with
|
|
|
|
|
|
low-molecular weight heparin is allowed)
|
|
|
|
|
|
Serious grade 4 venous thromboembolic event including pulmonary embolism
|
|
|
|
|
|
Moderate to severe proteinuria as demonstrated by urine dipstick for proteinuria ≥2+
|
|
|
|
|
|
For patients with ≥2+ proteinuria on dipstick urinalysis, a urine protein: creatinine
|
|
|
|
|
|
(UPC) ratio will be determined, or a 24-hour urine collection will be done. Patients
|
|
|
|
|
|
with a UPC ratio <1 or a 24-hour urine protein <1 gram are eligible
|
|
|
|
|
|
History of abdominal fistula or gastrointestinal perforation, or serious GI bleeding
|
|
|
|
|
|
within 6 months
|
|
|
|
|
|
History of severe arterial thromboembolic event within 12 months of start of study
|
|
|
|
|
|
drug
|
|
|
|
|
|
Major surgery within 4 weeks prior to initiation of study treatment. (If the
|
|
|
|
|
|
participant had major surgery, the participant must have recovered adequately from the
|
|
|
|
|
|
procedure and/or any complications from the surgery prior to starting study
|
|
|
|
|
|
intervention)
|
|
|
|
|
|
A known history of severe hypersensitivity (≥Grade 3) to study drugs and/or any of its
|
|
|
|
|
|
excipients
|
|
|
|
|
|
Has had an allogenic tissue/solid organ transplant
|
|
|
|
|
|
Unable to participate in the trial according to the investigator's decision
|
|
|
|
|
|
Have received a live vaccine within 30 days prior to enrolment. Seasonal flu vaccines
|
|
|
|
|
|
that do not contain live virus are permitted
|
|
|
|
|
|
Have had a serious or non-healing wound, ulcer, or bone fracture within 28 days prior
|
|
|
|
|
|
to enrolment
|
|
|
|