| Eligibility |
Inclusion criteria for the first phase randomized control period:
- Voluntarily agree to participate in the study and sign the informed consent form.
- 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.
- Expected survival = 12 weeks.
- ECOG PS score 0 or 1.
- 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.
With Adequate Organ Function
- Bone marrow function:
Hemoglobin = 9 g/dL; Absolute neutrophil count = 1.5×109/L; Platelets = 100 × 109/L;
- Liver function (based on the normal values specified by study site):
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;
- Renal function (based on the normal values specified by study site):
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;
- Cardiac function:
New York Heart Association (NYHA) classification < Grade III; Left ventricular ejection
fraction = 50%; Tumor Related Criteria
- Histologically and/or cytologically confirmed invasive locally advanced or metastatic
breast cancer that is incurable and unresectable;
- Positive HER2 expression (positive defined as: IHC 3+ or FISH+); previous test results
of HER2 expression provided by the subjects (have to be confirmed by the investigator)
and those obtained from the study site or the central laboratory were both acceptable;
subject are able to provide samples from primary or metastatic tumor sites for HER2
test (either paraffin blocks, paraffin-embedded sections, or sections prepared using
freshly excised tissues);
- With prior taxane therapy (monotherapy or in combination with other drugs, treatment
duration should be = 2 cycles);
- With prior adjuvant therapy, have received treatment with trastuzumab or its
biosimilar for patients with locally advanced cancer or metastasis during relapse and
metastasis (monotherapy or in combination with other drugs, such as for = 3 months in
the adjuvant therapy phase, and = 6 weeks in the post-relapse and metastatic phase);
- With evidence of tumor progression during or after the most recent treatment as
confirmed by the investigator or with documented history;
- No more than 2 lines of chemotherapy received after relapse/metastasis. The number of
chemotherapy lines is restricted to chemotherapeutic drugs, and each chemotherapy
regimen is counted as a number of chemotherapy line, excluding targeted drugs and/or
endocrine drugs; the same maintenance treatment as the previous chemotherapy regimen
will not be counted.
- With at least one measurable lesion per RECIST v1.1.
Exclusion Criteria for Randomized Controlled Period in Stage I:
- Use of investigational drugs within 4 weeks prior to study treatment;
- 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;
- 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.;
- Currently suffering from active infections requiring systemic treatment;
- With history of active tuberculosis;
- With positive HIV test result;
- Patients with active hepatitis B or C (HBsAg positive and HBV DNA positive; HCVAb
positive);
- Presence of effusion in the third space (including massive hydrothorax or ascites)
that cannot be controlled by drainage or other methods;
- With known hypersensitivity or delayed-type hypersensitivity to certain components of
RC48-ADC, capecitabine, lapatinib or similar drugs;
- With pre-existing gastrointestinal disorders that may affect absorption, such as
ileus, ulcerative colitis, chronic diarrhea, inability to swallow, and other
conditions that may affect drug administration and absorption;
- 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;
- Women who are pregnant or during lactation period or women/men with childbearing
plans;
- Subjects who are estimated to have poor compliance with the clinical study or the
investigator determines that there are other factors not appropriate to participate in
the study;
- Presence of brain metastases and/or carcinomatous meningitis.
- Had any other malignancy within 5 years prior to signing of the informed consent
(except for non-melanoma skin cancer, cervix carcinoma in situ or other tumor that
have been effectively treated and considered to be cured);
- Have received prior chemotherapy, radiotherapy, immunotherapy within 4 weeks prior to
the first dose of the study drug;
- Have received hormonal therapy for breast cancer within 2 weeks prior to the start of
study treatment;
- Patients who received palliative radiotherapy for bone metastases within 2 weeks
before the start of study treatment;
- Have received anti-tumor traditional Chinese medicine within 2 weeks prior to the
start of study treatment;
- Have received capecitabine within 6 months prior to the start of study treatment, or
have failed to respond to prior treatment with capecitabine (including progression
while on capecitabine treatment or maintenance of clinical efficacy for a period of
less than 6 months after treatment), or with intolerance to capecitabine. Patients who
have received capecitabine as adjuvant therapy and have discontinued this therapy for
= 6 months are eligible;
- 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;
- With prior systemic therapy with or participation in clinical studies with HER2
tyrosine kinase inhibitors (TKIs);
- With prior treatment with T-DM1 or had participated in clinical studies with same
class of drugs.
- 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.;
- Currently suffering from active infections requiring systemic treatment;
- With positive HIV test result;
- 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;
- Women who are pregnant or in lactation period or women/men with childbearing plans;
- 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;
- ECOG PS score 0 or 1;
- 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.
With Adequate Organ Function
- Bone marrow function:
Hemoglobin = 9 g/dL; Absolute neutrophil count = 1.5×109/L; Platelets = 100 × 109/L;
- Liver function (based on the normal values specified by study site):
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;
- Renal function (based on the normal values specified by study site):
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;
- Cardiac function:
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.
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