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Voluntarily agree to participate in the study and sign the informed consent form |
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Subjects aged 18 - 70 years (inclusive), and the subject who have not reached the age of 71 years old will be considered to be ≤ 70 years of age |
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Expected survival ≥ 12 weeks |
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ECOG PS score 0 or 1 |
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Female subjects should be surgically sterilized or in post-menopausal status, or agree to use at least one medically accepted contraceptive methods (such as intrauterine device, contraceptive drug or condom) during study treatment period and for up to 6 months after the study treatment is completed, and the blood pregnancy test must be negative within 7 days prior to study enrollment, and they must not be lactating. For male subjects: all the subjects should be surgically sterilized or agree to use one of the medically approved contraceptive methods during the study treatment period and for an additional of 6 months after the end of the study treatment period |
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Able to understand study requirements, willing and able to comply with study protocol and follow-up procedures |
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With Adequate Organ Function |
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Bone marrow function |
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Hemoglobin ≥ 9 g/dL; Absolute neutrophil count ≥ 1.5×109/L; Platelets ≥ 100 × |
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Liver function (based on the normal values specified by study site) |
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L |
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Serum total bilirubin ≤ 1.5 × the upper limit of normal (ULN); Alanine aminotransferase |
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(ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 × ULN in the |
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absence of liver metastases, while ALT, AST and ALP ≤ 5 × ULN in the presence of liver |
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Renal function (based on the normal values specified by study site) |
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metastases |
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Serum creatinine ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 60 mL/min as calculated by |
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Cardiac function |
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Cockcroft-Gault formula, or 24-hour urine Crcl ≥ 60 mL/min |
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New York Heart Association (NYHA) classification < Grade III; Left ventricular ejection |
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fraction ≥ 50%; Tumor Related Criteria |
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Histologically and/or cytologically confirmed invasive locally advanced or metastatic |
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breast cancer that is incurable and unresectable |
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Positive HER2 expression (positive defined as: IHC 3+ or FISH+); previous test results |
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of HER2 expression provided by the subjects (have to be confirmed by the investigator) |
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and those obtained from the study site or the central laboratory were both acceptable |
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With at least one measurable lesion per RECIST v1.1 |
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subject are able to provide samples from primary or metastatic tumor sites for HER2 |
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test (either paraffin blocks, paraffin-embedded sections, or sections prepared using |
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freshly excised tissues) |
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With prior taxane therapy (monotherapy or in combination with other drugs, treatment |
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duration should be ≥ 2 cycles) |
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With prior adjuvant therapy, have received treatment with trastuzumab or its |
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biosimilar for patients with locally advanced cancer or metastasis during relapse and |
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metastasis (monotherapy or in combination with other drugs, such as for ≥ 3 months in |
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the adjuvant therapy phase, and ≥ 6 weeks in the post-relapse and metastatic phase) |
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With evidence of tumor progression during or after the most recent treatment as |
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confirmed by the investigator or with documented history |
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No more than 2 lines of chemotherapy received after relapse/metastasis. The number of |
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chemotherapy lines is restricted to chemotherapeutic drugs, and each chemotherapy |
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regimen is counted as a number of chemotherapy line, excluding targeted drugs and/or |
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endocrine drugs; the same maintenance treatment as the previous chemotherapy regimen |
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will not be counted |
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Use of investigational drugs within 4 weeks prior to study treatment
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Currently suffering from active infections requiring systemic treatment
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With history of active tuberculosis
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With positive HIV test result
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Presence of brain metastases and/or carcinomatous meningitis
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Have received major surgeries within 4 weeks prior to study treatment and have not
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recovered yet
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Have received a live vaccine inoculation within 4 weeks prior to the start of study
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drug administration or was scheduled to receive any vaccine during the study
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Have experienced arterial/venous thromboembolic events, such as cerebrovascular
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accident (including transient ischemic attack), deep vein thrombosis and pulmonary
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embolism within 1 year prior to the initiation of study treatment
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Suffering uncontrolled systemic diseases, including diabetes, hypertension, pulmonary
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fibrosis, acute lung disease, interstitial lung disease, cirrhosis, etc
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Patients with active hepatitis B or C (HBsAg positive and HBV DNA positive; HCVAb
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positive)
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Presence of effusion in the third space (including massive hydrothorax or ascites)
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that cannot be controlled by drainage or other methods
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With known hypersensitivity or delayed-type hypersensitivity to certain components of
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RC48-ADC, capecitabine, lapatinib or similar drugs
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Currently suffering from active infections requiring systemic treatment
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With pre-existing gastrointestinal disorders that may affect absorption, such as
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With positive HIV test result
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ileus, ulcerative colitis, chronic diarrhea, inability to swallow, and other
|
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conditions that may affect drug administration and absorption
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With known psychiatric disorders or drug abuse disorders that might have an impact on
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compliance with protocol requirements
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Have any other diseases, metabolic disorders, abnormal physical examination findings
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or abnormal laboratory test results, which, judged by the investigator, are reasonably
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Women who are pregnant or in lactation period or women/men with childbearing plans
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to suspect a disease or condition as a contraindication of the study drug, or may
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interfere the interpretation of the study results in the future, or that put the
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patient at a high risk
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Women who are pregnant or during lactation period or women/men with childbearing
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plans
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Subjects who are estimated to have poor compliance with the clinical study or the
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investigator determines that there are other factors not appropriate to participate in
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the study
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Had any other malignancy within 5 years prior to signing of the informed consent
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(except for non-melanoma skin cancer, cervix carcinoma in situ or other tumor that
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have been effectively treated and considered to be cured)
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Have received prior chemotherapy, radiotherapy, immunotherapy within 4 weeks prior to
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the first dose of the study drug
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ECOG PS score 0 or 1
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Have received hormonal therapy for breast cancer within 2 weeks prior to the start of
|
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|
study treatment
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Patients who received palliative radiotherapy for bone metastases within 2 weeks
|
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|
With Adequate Organ Function
|
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|
|
before the start of study treatment
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|
Bone marrow function
|
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Have received anti-tumor traditional Chinese medicine within 2 weeks prior to the
|
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|
|
start of study treatment
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Liver function (based on the normal values specified by study site)
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Have received capecitabine within 6 months prior to the start of study treatment, or
|
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|
|
have failed to respond to prior treatment with capecitabine (including progression
|
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|
|
while on capecitabine treatment or maintenance of clinical efficacy for a period of
|
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|
|
|
|
less than 6 months after treatment), or with intolerance to capecitabine. Patients who
|
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|
|
|
have received capecitabine as adjuvant therapy and have discontinued this therapy for
|
|
|
|
|
|
Renal function (based on the normal values specified by study site)
|
|
|
|
|
|
≥ 6 months are eligible
|
|
|
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|
|
The toxicity of prior anti-tumor therapy had not recovered to CTCAE [Version 4.03]
|
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|
|
|
Grade 0-1, with the following exceptions: a). alopecia; b). pigmentation; c)
|
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|
|
Cardiac function
|
|
|
|
|
|
long-term toxicity caused by radiotherapy, which are considered as irreversible by the
|
|
|
|
|
|
investigator
|
|
|
|
|
|
With prior systemic therapy with or participation in clinical studies with HER2
|
|
|
|
|
|
tyrosine kinase inhibitors (TKIs)
|
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|
|
With prior treatment with T-DM1 or had participated in clinical studies with same
|
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|
|
class of drugs
|
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|
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|
|
With known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase
|
|
|
|
|
|
deficiency
|
|
|
|
|
|
Inclusion Criteria for Stage 1 Cross-over Period：
|
|
|
|
|
|
Had previously participated in the study of randomized controlled period and received
|
|
|
|
|
|
lapatinib plus capecitabine, and received no anti-tumor treatment after disease
|
|
|
|
|
|
progression (RECIST v1.1 criteria)
|
|
|
|
|
|
The general situation part refers to the selection criteria of the first stage
|
|
|
|
|
|
randomized control period
|
|
|
|
|
|
Exclusion Criteria for Cross-over Period in Stage I：
|
|
|
|
|
|
Have received major surgeries within 4 weeks prior to study treatment and have not
|
|
|
|
|
|
recovered yet
|
|
|
|
|
|
Have received a live vaccine inoculation within 4 weeks prior to the start of study
|
|
|
|
|
|
drug administration or was scheduled to receive any vaccine during the study (except
|
|
|
|
|
|
the COVID-19 vaccine)
|
|
|
|
|
|
Have experienced arterial/venous thromboembolic events, such as cerebrovascular
|
|
|
|
|
|
accident (including transient ischemic attack), deep vein thrombosis and pulmonary
|
|
|
|
|
|
embolism within 1 year prior to the initiation of study treatment
|
|
|
|
|
|
Suffering uncontrolled systemic diseases, including diabetes, hypertension, pulmonary
|
|
|
|
|
|
fibrosis, acute lung disease, interstitial lung disease, cirrhosis, etc
|
|
|
|
|
|
Patients with active hepatitis B or C (HBsAg positive and HBV DNA positive; HCVAb
|
|
|
|
|
|
positive)
|
|
|
|
|
|
Presence of effusiona in the third space (including massive hydrothorax or ascites)
|
|
|
|
|
|
that cannot be controlled by drainage or other means
|
|
|
|
|
|
With known hypersensitivity or delayed-type hypersensitivity to certain components of
|
|
|
|
|
|
RC48-ADC or similar drugs
|
|
|
|
|
|
With known psychiatric disorders or drug abuse disorders that might have an impact on
|
|
|
|
|
|
compliance with protocol requirements
|
|
|
|
|
|
Have any other diseases, metabolic disorders, abnormal physical examination findings
|
|
|
|
|
|
or abnormal laboratory test results, which, judged by the investigator, are reasonably
|
|
|
|
|
|
to suspect a disease or condition as a contraindication of the study drug, or may
|
|
|
|
|
|
interfere the interpretation of the study results in the future, or that put the
|
|
|
|
|
|
patient at a high risk
|
|
|
|
|
|
Subjects who are estimated to have poor compliance with the protocol of this
|
|
|
|
|
|
cross-over period or the investigator determines that there are other factors not
|
|
|
|
|
|
appropriate to participate in the study
|
|
|
|
|
|
Presence of brain metastases and/or carcinomatous meningitis. Have received prior
|
|
|
|
|
|
treatment for brain metastases may be considered for participating in this study
|
|
|
|
|
|
provided that the diseases were stable, had no disease progression as confirmed by
|
|
|
|
|
|
imaging examinations within 4 weeks prior to the first dose of the investigational
|
|
|
|
|
|
product (IP), and that all neurological symptoms have recovered to baseline level
|
|
|
|
|
|
without any evidence of newly emerging or spread brain metastases; moreover, treatment
|
|
|
|
|
|
with radiation, surgery or steroids was discontinued at least 14 days prior to the
|
|
|
|
|
|
first dose of study drug. This exception did not include cancerous meningitis, which
|
|
|
|
|
|
should be excluded regardless of the stability of its clinical status
|
|
|
|
|
|
Patients who received palliative radiotherapy for bone metastases within 2 weeks
|
|
|
|
|
|
before the start of study treatment
|
|
|
|
|
|
Received treatment with lapatinib and/or capecitabine within 2 weeks prior to the
|
|
|
|
|
|
first dose of the study drug
|
|
|
|
|
|
The toxicity of prior anti-tumor therapy had not recovered to CTCAE [Version 4.03]
|
|
|
|
|
|
Grade 0-1, with the following exceptions: a). alopecia; b). pigmentation; c)
|
|
|
|
|
|
long-term toxicity caused by radiotherapy, which are considered as irreversible by the
|
|
|
|
|
|
investigator
|
|
|
|
|
|
Inclusion Criteria for Randomized Controlled Period in Stage II：
|
|
|
|
|
|
The general situation part refers to the selection criteria of the first stage
|
|
|
|
|
|
randomized control period
|
|
|
|
|
|
Exclusion Criteria for Randomized Controlled Period in Stage II：
|
|
|
|
|
|
The toxicity of prior anti-tumor therapy had not recovered to CTCAE [Version 5.0]
|
|
|
|
|
|
Grade 0-1, with the following exceptions: a). alopecia; b). pigmentation; c)
|
|
|
|
|
|
long-term toxicity caused by radiotherapy, which are considered as irreversible by the
|
|
|
|
|
|
investigator
|
|
|
|
|
|
The remaining parts refer to the exclusion criteria of the first stage randomized
|
|
|
|
|
|
control period
|
|
|
|
|
|
Inclusion Criteria for Cross-over Period in Stage II：
|
|
|
|
|
|
Had previously participated in the study of randomized controlled period and received
|
|
|
|
|
|
lapatinib plus capecitabine, and received no anti-tumor treatment after disease
|
|
|
|
|
|
progression (RECIST v1.1 criteria)
|
|
|
|
|
|
Expected survival ≥ 12 weeks
|
|
|
|
|
|
Female subjects should be surgically sterilized or in post-menopausal status, or agree
|
|
|
|
|
|
to use at least one medically accepted contraceptive methods (such as intrauterine
|
|
|
|
|
|
device, contraceptive drug or condom) during study treatment period and for up to 6
|
|
|
|
|
|
months after the study treatment is completed, and the blood pregnancy test must be
|
|
|
|
|
|
negative within 7 days prior to study enrollment, and they must not be lactating. For
|
|
|
|
|
|
male subjects: all the subjects should be surgically sterilized or agree to use one of
|
|
|
|
|
|
the medically approved contraceptive methods during the study treatment period and for
|
|
|
|
|
|
an additional of 6 months after the end of the study treatment period
|
|
|
|
|
|
Able to understand study requirements, willing and able to comply with study protocol
|
|
|
|
|
|
and follow-up procedures
|
|
|
|
|
|
Hemoglobin ≥ 9 g/dL; Absolute neutrophil count ≥ 1.5×109/L; Platelets ≥ 100 × 109/L
|
|
|
|
|
|
Serum total bilirubin ≤ 1.5 × the upper limit of normal (ULN); Alanine aminotransferase
|
|
|
|
|
|
(ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 × ULN in the
|
|
|
|
|
|
absence of liver metastases, while ALT, AST and ALP ≤ 5 × ULN in the presence of liver
|
|
|
|
|
|
metastases
|
|
|
|
|
|
Serum creatinine ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 60 mL/min as calculated by
|
|
|
|
|
|
Cockcroft-Gault formula, or 24-hour urine Crcl ≥ 60 mL/min
|
|
|
|
|
|
New York Heart Association (NYHA) classification < Grade III; Left ventricular ejection
|
|
|
|
|
|
fraction ≥ 50%
|
|
|
|
|
|
Exclusion Criteria for Cross-over Period in Stage II：
|
|
|
|
|
|
The toxicity of prior anti-tumor therapy had not recovered to CTCAE [Version 5.0]
|
|
|
|
|
|
Grade 0-1, with the following exceptions: a. alopecia; b. pigmentation; c. long-term
|
|
|
|
|
|
toxicity caused by radiotherapy, which are considered as irreversible by the
|
|
|
|
|
|
investigator
|
|
|
|
|
|
The remaining parts refer to the exclusion criteria of the first phase of the
|
|
|
|
|
|
crossover period
|
|
|
|