A Study of RC48-ADC Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer With or Without Liver Metastases

Sponsor

RemeGen Co., Ltd. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03500380

Collaborator

(none)

301

Enrollment

Locations

Arms

68.2

Anticipated Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, open, parallel-controlled, multicenter, phase II/III, seamless design clinical trial to compare the efficacy and safety of RC48-ADC with capecitabine + lapatinib in locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer and HER2-positive advanced breast cancer with liver metastasis.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms Breast Diseases Capecitabine HER2-positive Breast Cancer HER2 Positive Breast Carcinoma HER2-positive Advanced Breast With Liver Metastases	Drug: RC48-ADC Drug: Lapatinib Drug: Capecitabine	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

301 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Controlled, Multi-center Phase II Clinical Study to Evaluate the Efficacy and Safety of Recombinant Humanized Anti-HER2 Monoclonal Antibody-MMAE Conjugate for Injection in the Treatment of HER2-positive Locally Advanced or Metastatic Breast Cancer and Phase III Clinical Study to Evaluate the Efficacy and Safety of Recombinant Humanized Anti-HER2 Monoclonal Antibody-MMAE Conjugate for Injection in the Treatment of HER2-positive Advanced Breast With Liver Metastases

Actual Study Start Date :

Apr 24, 2018

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RC48-ADC Participants will receive RC48-ADC 2.0 mg/kg intravenous (IV) infusion each 14-day treatment cycle until disease progression (PD) (as assessed by the investigator), unmanageable toxicity, or study termination.	Drug: RC48-ADC RC48-ADC 2.0 mg/kg IV every 14 days Other Names: RC48
Active Comparator: Lapatinib + Capecitabine Participants will receive lapatinib 1250 mg orally once daily during each 21-day cycle + capecitabine 2000 mg/m^2 orally daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.	Drug: Lapatinib Lapatinib 1250 mg orally once daily during each 21-day cycle. Drug: Capecitabine Capecitabine 2000 mg/m^2 orally daily on Days 1-14 of each 21-day treatment cycle.

Arm

Intervention/Treatment

Experimental: RC48-ADC

Participants will receive RC48-ADC 2.0 mg/kg intravenous (IV) infusion each 14-day treatment cycle until disease progression (PD) (as assessed by the investigator), unmanageable toxicity, or study termination.

Drug: RC48-ADC

RC48-ADC 2.0 mg/kg IV every 14 days

Other Names:

RC48

Active Comparator: Lapatinib + Capecitabine

Participants will receive lapatinib 1250 mg orally once daily during each 21-day cycle + capecitabine 2000 mg/m^2 orally daily on Days 1-14 of each 21-day treatment cycle until PD (as assessed by the investigator), unmanageable toxicity, or study termination.

Drug: Lapatinib

Lapatinib 1250 mg orally once daily during each 21-day cycle.

Drug: Capecitabine

Capecitabine 2000 mg/m^2 orally daily on Days 1-14 of each 21-day treatment cycle.

Outcome Measures

Primary Outcome Measures

Progression-free Survival (PFS) as Assessed by an IRC [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
Tumor response was assessed by an IRC according to RECIST v1.1.

Secondary Outcome Measures

Progression-free Survival (PFS) as Assessed by Investigator [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
Tumor response was assessed by investigator according to RECIST v1.1.
Objective Response Rate （ORR） [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR).
Duration of Objective Response (DOR) [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
DOR was defined as the time from first documented OR to first documented PD or death from any cause, whichever occurred earlier.
Clinical Benefit Rate （CBR） [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
Participants were considered as experienced clinical benefit if they had an OR or maintained stable disease (SD) for at least 6 months from randomization. OR: CR or PR determined on 2 consecutive tumor assessments >/=4 weeks apart.
Time to Treatment Failure [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]
Time to treatment failure was defined as the time from randomization to discontinuation of treatment for any reason, including PD (per investigator review), treatment toxicity, or death from any cause.
Overall Survival [From date of randomization until the date of death from any cause, assessed up to 48 months]
OS was defined as the time from the date of randomization to the date of death from any cause.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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):

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cancer Hospital Chinese Academy of Medical Sciences	Beijing	Beijing	China	100021
2	Liaoning Cancer Hospital & Institute	Shenyang	Liaoning	China
3	The First Hospital of China Medical University	Shenyang	Liaoning	China
4	An Yang Cancer Hospital	Anyang		China
5	Beijing Luhe Hospital	Beijing		China
6	Peking University People's Hospital	Beijing		China
7	The First Affiliated Hospital of Bengbu Medical College	Bengbu		China
8	Bin Zhou No.1 People's Hospital	Binzhou		China
9	Jilin Cancer Hospital	Changchun		China
10	The First Hospital Jilin University	Changchun		China
11	The First Hospital of Jilin University	Changchun		China
12	Hunan Cancer Hospital	Changsha		China
13	The Second Xiyang Hospital of Central South University	Changsha		China
14	Xiangya Hospital Central South University	Changsha		China
15	Heping Hospital Affiliated to Changzhi Medical College	Changzhi		China
16	Affiliated Hospital of Chengde Medical University	Chengde		China
17	West China Hospital,Sichuan University	Chengdu		China
18	Chongqing University Three gorges Hospital	Chongqing		China
19	The Southwest Hospital of AMU	Chongqing		China
20	The Second Hospital of Dalian Medical University	Dalian		China
21	Fujian Cancer Hospital	Fuzhou		China
22	Guangdong Provincial People's Hospital	Guangzhou		China
23	Sun Yat-Sen Memorial Hospital	Guangzhou		China
24	The Affiliated Tumor Hospital of Guangzhou Medical University	Guangzhou		China
25	Guizhou Cancer Hospital	Guiyang		China
26	Harbin Medical University Cancer Hospital	Ha'erbin		China
27	The First Affiliated Hospital of Medical School of Zhejiang University	Hangzhou		China
28	The Second Affiliated Hospital of Zhejiang University School of Medicine	Hangzhou		China
29	Zhejiang Cancer Hospital	Hangzhou		China
30	Anhui Cancer Hospital	Hefei		China
31	Anhui Province Hospital	Hefei		China
32	The First Affiliated Hospital of Anhui Medical University	Hefei		China
33	Qilu Hospital of Shandong University	Jinan		China
34	The First People's Hospital of Jining	Jining		China
35	Yunnan Cancer Hospital	Kunming		China
36	Linyi Cancer Hospital	Linyi		China
37	The First Affiliated Hospital of Henan University of Science & Technology	Luoyang		China
38	Jiangsu Cancer Hospital	Nanjing		China
39	The Affiliated Tumor Hospital of Guangxi Medical University	Nanning		China
40	The Second People's Hospital of Neijiang	Neijiang		China
41	Hospital of Qingdao University	Qingdao		China
42	Fudan University Shanghai Cancer Center	Shanghai		China
43	Shanghai Changhai Hospital	Shanghai		China
44	Shanghai Ruijin Hospital	Shanghai		China
45	Cancer Hospital of Shantou University Medical College	Shantou		China
46	Yue Bei People's Hospital	Shaoguan		China
47	The Fourth Hospital of Hebei Medical University	Shijiazhuang		China
48	Tai'an City Central Hospital	Tai'an		China
49	Shanxi Bethune Hospital	Taiyuan		China
50	Shanxi Cancer Hospital	Taiyuan		China
51	Taizhou Enze Medical Center	Taizhou		China
52	Tianjin Cancer Hospitial	Tianjin		China
53	Weihai Municipal Hospital	Weihai		China
54	Hubei Cancer Hospital	Wuhan		China
55	Tongji Medical College of HUST	Wuhan		China
56	Wuhan Union Hospital	Wuhan		China
57	The First Affiliated Hospital of the Fourth Military University of P.L.A.	Xi'an		China
58	The First Affiliated Hospital of Xi'an Jiaotong University	Xi'an		China
59	Xing Tai People's Hospital	Xingtai		China
60	The First Affiliated Hospital of Xinxiang Medical University	Xinxiang		China
61	The Affiliated Hospital of Xuzhou Medical University	Xuzhou		China
62	Xuzhou Central Hospital	Xuzhou		China
63	Yanbian University Hospital	Yanbian		China
64	Yantai Yuhuangding Hospital	Yantai		China
65	Yuncheng Central Hospital	Yuncheng		China
66	Henan Cancer Hospital	Zhengzhou		China
67	The First Affiliated Hospital of Zhengzhou University	Zhengzhou		China