Clinical trial NCT04400695: A Study of RC48-ADC for the Treatment of Locally Advanced or Metastatic Breast Cancer With Low Expression of HER2
Official title: Randomized, Controlled, Multicenter Phase III Clinical Study Evaluating the Efficacy and Safety of RC48-ADC for the Treatment of Locally Advanced or Metastatic Breast Cancer With Low Expression of HER2
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Lead sponsor: RemeGen Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2020-05-22
Enrollment: 366
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will compare RC48-ADC to physician choice standard treatment. Participants must have HER2-low breast cancer ，previous use of anthracyclines, and have been treated with one or two systemic chemotherapy regimens following recurrence/metastasis.

Detailed description: This study is a multi-center, randomized, open, parallel control to evaluate the effectiveness and safety of Phase III clinical trials of the efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody-Monomethyl auristatin E (MMAE) conjugate for the treatment of locally advanced or metastatic breast cancer the study.The low expression of HER2 is defined as: the immunohistochemistry (IHC) confirmed by the central laboratory detects the expression of HER2 protein as IHC 2+ and the fluorescence in situ hybridization (FISH) detection has no amplification.

Eligibility criteria: Inclusion Criteria:

* Voluntarily agree to participate in the study and sign the informed consent;
* Subjects aged 18-70 years (including 18 years and 70 years) and not reaching the 71st birthday were all considered to be ≤70 years old;
* Expected survival ≥12 weeks;
* Eastern Cooperative Oncology Group(ECOG) physical condition 0 or 1;
* For female subjects of child-bearing age women agreed to study during treatment and experimental subjects within 6 months after the end of the treatment period using an approved by the medical contraception (e.g. intrauterine device, the pill or condoms), before the study drug delivery within 7 days of pregnancy blood test must be negative (sterilization surgery or age 60 or more subjects can choose no pregnancy blood test), and must be an lactation. For male subjects: should be sterilized surgically, or agree to use a medically approved contraceptive method during the study period and for 6 months after the end of the treatment period. Control subjects after the end of the treatment period according to the choice of control drugs to determine the length of contraception.
* Able to understand the study requirements and be willing and able to follow the study and follow-up procedures.
* Bone marrow function:

hemoglobin ≥9g/dL; absolute neutrophil count ≥1.5×109/L; white blood cell count ≥3.0×109/L platelet ≥100 ×109/L;

* Liver function (according to the normal value of the clinical trial center) :

serum total bilirubin ≤1.5 times the upper limit of normal value (ULN); alanine aminotransferase (ALT), aspartate aminotransferase(AST) and Alkaline phosphatase（ALP） were ≤2.5 × ULN in the absence of liver metastasis, and ALT, AST and Alkaline phosphatase(ALP) were ≤5 × ULN in the presence of liver metastasis

* Renal function (according to the normal value of the clinical trial center) :

serum creatinine ≤1.5×ULN, or calculated by Cockcroft-Gault formula, the creatinine clearance rate (CrCl) ≥60 mL/min;

* Cardiac function:

American New York college of cardiology (NYHA) grade \< 3; left ventricular ejection fraction ≥50%;

* Breast cancer subjects diagnosed by histology and / or cytology are currently at a locally advanced or metastatic stage and cannot be radically removed;
* The low expression of HER2 confirmed by the IHC and FISH results of the central laboratory (defined as: IHC 2+ and no amplification of FISH); the subject can provide a specimen of the primary or metastatic tumor site (paraffin wax) for HER2 detection Block, paraffin-embedded section or fresh tissue section can be used);
* Previous use of anthracycline drugs;
* Received 1 or 2 systemic chemotherapy treatments after relapse / metastasis. Subjects who relapsed during adjuvant chemotherapy or within 12 months after the end of adjuvant chemotherapy were considered to have failed first-line chemotherapy after relapse / metastasis.
* Hormone receptors are negative or positive. Hormone receptor-positive subjects need to progress after receiving endocrine therapy after relapse / metastasis or relapse after less than 2 years. Patients who are not suitable for endocrine therapy can be included in this study after undergoing chemotherapy treatment (first-line or second-line);
* The imaging evidence confirmed by the investigator that the tumor disease progressed during or after the most recent treatment is required;
* There has been no diagnosis of HER2 positive (HER2 IHC 3+ or FISH amplification)
* Have not used drugs targeting HER2 (including antibodies, small molecule Tyrosine kinase inhibitor（TKIs） and antibody drug conjugates).
* According to the RECIST 1.1 standard, there is at least one measurable lesion.

Exclusion Criteria:

* Received chemotherapy within 4 weeks before the start of study administration (treatment with nitrosourea and mitomycin C within 6 weeks, oral fluorouracil within 2 weeks), radiotherapy (palliative for bone metastases Local radiotherapy is within 2 weeks before study administration), immunotherapy; received endocrine therapy for breast cancer within 2 weeks before study administration;
* The research drug was used within 4 weeks before the start of study administration;
* Have undergone major surgery within 4 weeks before the start of study administration;
* Have received a live vaccine within 4 weeks before the start of study administration or plan to receive any vaccine during the study period;
* Serious cardiovascular and cerebrovascular events occurred within 12 months, including but not limited to unstable angina, myocardial infarction, cerebral hemorrhage, and cerebral infarction (except for asymptomatic and untreated lacunar infarction)；
* Those who are suffering from heart disease are not suitable for enrollment, including but not limited to arrhythmia and heart failure requiring medical treatment or accompanied by symptoms;
* There are other lung diseases requiring treatment or serious, including but not limited to active pulmonary tuberculosis, interstitial lung disease, etc ;
* Suffering from active infection requiring systemic treatment;
* Have active autoimmune diseases (such as the use of corticosteroids or immunosuppressive drugs, etc.) that require systemic treatment within the past 2 years, allowing related alternative treatments (such as thyroxine, insulin, or the physiology of adrenal or pituitary insufficiency Corticosteroid replacement therapy);
* The toxicity of the previous anti-tumor therapy has not been restored to the 0 to 1 level defined by CTCAE version 5.0, of which the neurotoxicity has not been restored to 0; except for hair loss, pigmentation or other researches that do not increase the risk of medication Happening;
* Have a clear past or current history of neurological or mental disorders, including epilepsy or dementia;
* According to the investigator's judgment, there are concomitant diseases that seriously endanger the safety of the subject or affect the completion of the clinical study；
* Positive HIV test results; patients with active hepatitis B or C (HBsAg positive and hepatitis B virus（HBV） DNA titers above the upper limit of normal; Hepatitis C Virus Antibody(HCVAb) positive hepatitis C virus （HCV） RNA titers above the upper limit of normal)；
* There is a third interstitial fluid that cannot be controlled by drainage or other methods (including a large amount of pleural effusion or ascites);
* Known hypersensitivity or delayed allergic reaction to certain components of RC48-ADC or similar drugs;
* Subjects who are not suitable for using any of the alternative control drugs;
* The presence of brain metastases and / or cancerous meningitis;
* Have other malignant tumors within 5 years before signing the informed consent form (except for non-melanoma skin cancer, cervical carcinoma in situ or other tumors that have been effectively treated, except malignant tumors that are considered cured);
* Subjects who are estimated to be inadequate for patients to participate in this clinical study or other factors that the investigator believes are inappropriate to participate in this study;

Primary outcomes:
measure: Progression-free survival (PFS), evaluated by an independent efficacy evaluation committee
timeFrame: within approximately 3 years
Secondary outcomes:
measure: Progression-free survival (PFS), evaluated by the investigator
timeFrame: within approximately 3 years
measure: Objective remission rate (ORR)
timeFrame: within approximately 3 years
measure: Duration of relief (DOR)
timeFrame: within approximately 3 years
measure: Disease control rate (DCR)
timeFrame: within approximately 3 years
measure: Tumor progression time (TTP)
timeFrame: within approximately 3 years
measure: Overall survival (OS)
timeFrame: within approximately 3 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Oncology Hospital, Chinese Academy of Medical Sciences
state: Beijing
Study officials:
affiliation: Oncology Hospital, Chinese Academy of Medical Sciences
name: Binghe Xu
role: PRINCIPAL_INVESTIGATOR
affiliation: Liaoning Cancer Hospital & Institute
name: Tao Sun
role: PRINCIPAL_INVESTIGATOR
affiliation: Jilin University First Hospital
name: Wei Li
role: PRINCIPAL_INVESTIGATOR
affiliation: First Affiliated Hospital of China Medical University
name: Yuee Teng
role: PRINCIPAL_INVESTIGATOR
affiliation: Peking University People's Hospital
name: Shu Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Zhejiang Cancer Hospital
name: Xiaojia Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Henan Cancer Hospital
name: Min Yan
role: PRINCIPAL_INVESTIGATOR
affiliation: Jiangsu Cancer Institute & Hospital
name: Jifeng Feng
role: PRINCIPAL_INVESTIGATOR
affiliation: Jilin Provincial Tumor Hospital
name: Ying Cheng
role: PRINCIPAL_INVESTIGATOR
affiliation: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
name: Ying Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Sun Yat-sen University Cancer Prevention and Control Center
name: Ying Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Guangdong Provincial People's Hospital
name: Ning Liao
role: PRINCIPAL_INVESTIGATOR
affiliation: Qingdao University Hospital
name: Haibo Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Hunan Cancer Hospital
name: Quchang Ouyang
role: PRINCIPAL_INVESTIGATOR
affiliation: Anhui Provincial Hospital
name: Yueyin Pan
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Anhui Medical University
name: Yingying Du
role: PRINCIPAL_INVESTIGATOR
affiliation: Anhui Provincial Cancer Hospital
name: Changlu Hu
role: PRINCIPAL_INVESTIGATOR
affiliation: Tianjin Cancer Hospital
name: Zhongsheng Tong
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine
name: Jin Yang
role: PRINCIPAL_INVESTIGATOR
affiliation: Shandong Cancer Hospital and Institute
name: Lihua Song
role: PRINCIPAL_INVESTIGATOR
affiliation: Qilu Hospital of Shandong University
name: Xiuwen Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: West China Hospital
name: Yu Jiang
role: PRINCIPAL_INVESTIGATOR
affiliation: Hebei Medical University Fourth Hospital
name: Yunjiang Liu
role: PRINCIPAL_INVESTIGATOR
affiliation: Wuhan Union Hospital, China
name: Jing Cheng
role: PRINCIPAL_INVESTIGATOR
affiliation: Tongji Hospital
name: Huihua Xiong
role: PRINCIPAL_INVESTIGATOR
affiliation: Hubei Cancer Hospital
name: Xinhong Wu
role: PRINCIPAL_INVESTIGATOR
affiliation: Zhejiang University
name: Peng Shen
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Hospital Affiliated to Guangxi Medical University
name: Weimin Xie
role: PRINCIPAL_INVESTIGATOR
affiliation: Chongqing University Cancer Hospital
name: Xin Zhou
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Hospital of Guizhou Province
name: Li Ran
role: PRINCIPAL_INVESTIGATOR
affiliation: Shanxi Province Cancer Hospital
name: Yu Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Bethune Hospital of Shanxi Province
name: Jinnan Gao
role: PRINCIPAL_INVESTIGATOR
affiliation: Linyi Cancer Hospital
name: Jingfen Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: Yantai Yuhuangding Hospital
name: Liangming Zhang
role: PRINCIPAL_INVESTIGATOR
affiliation: First Affiliated Hospital of Fujian Medical University
name: Xianhe Xie
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Xiamen University
name: Ru Zeng
role: PRINCIPAL_INVESTIGATOR
affiliation: Weihai Municipal Hospital
name: Airong Wang
role: PRINCIPAL_INVESTIGATOR
affiliation: The Affiliated Hospital of Xuzhou Medical University
name: Zhengqiu Zhu
role: PRINCIPAL_INVESTIGATOR
affiliation: Xuzhou Central Hospital
name: Sanyuan Sun
role: PRINCIPAL_INVESTIGATOR
affiliation: Affiliated Hospital of Chengde Medical College
name: Qingshan Li
role: PRINCIPAL_INVESTIGATOR
affiliation: Affiliated Hospital of Hebei University
name: Aimin Zang
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Xinxiang Medical College
name: Liuzhong Yang
role: PRINCIPAL_INVESTIGATOR
affiliation: Jinan Central Hospital
name: Meili Sun
role: PRINCIPAL_INVESTIGATOR
affiliation: Zibo Central Hospital
name: Liang Li
role: PRINCIPAL_INVESTIGATOR
affiliation: Weifang People's Hospital
name: Guohua Yu
role: PRINCIPAL_INVESTIGATOR
affiliation: Neijiang Second People's Hospital
name: Xujuan Wang
role: PRINCIPAL_INVESTIGATOR
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