Study of SHR-A1811 Combined with Pyrotinib and Bevacizumab in Advanced Breast Cancer with Brain Metastasis

A Prospective, Single-arm, Exploratory, Phase Ib/II Study of SHR-A1811 Combined with Pyrotinib and Bevacizumab in Advanced Breast Cancer with Brain Metastasis.

In phase Ib, our study is aimed to evaluate the safety and tolerance of SHR-A1811 combined with pyrotinib in breast cancer with brain metastasis, and confirm the recommended phase 2 dose combined with preliminary results of efficacy.

In phase II, our study is aimed to evaluate the efficacy and safety of SHR-A1811 combined with pyrotinib and bevacizumab at RP2D in breast cancer with brain metastasis.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer Metastatic; Breast Cancer Brain Metastases
• Intervention / Treatment: Drug: SHR-A1811; Drug: Pyrotinib; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Estimated): 74
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Hongxia Wang, Chief physician; Phone Number: +8621-38196379; Email: whx365@126.com
• Study Contact Backup: Name: Ting Li, Associate chief physician; Phone Number: +86-18121299346; Email: cinderellaliting@126.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200230
      • Recruiting
      • Fudan Cancer Hospital
      • Contact: Hongxia Wang, Chief physician; Phone Number: +8621-38196379; Email: whx365@126.com
      • Contact: Ting Li, Associate chief physician; Phone Number: +86-18121299346; Email: cinderellaliting@126.com
      • Contact: Hongxia Wang, Chief physician
      • Contact: Biyun Wang, Chief physician

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• More than 18 years old;
• ECOG PS Score: 0~2;
• Patients must have a life expectancy ≥ 3 months;
• Brian metastasis confirmed by MRI, at least one measurable brain lesion based on RANO-BM with no prior radiotherapy;
• Mannitol or hormone therapy is allowed to use for brain metastasis before enrolment, but treatment dosage should be stable for one week and not need to be increased;
• Adequate organ function and marrow function;
• Has recovered from any AEs (≤ grade 1) related to prior anti-tumour treatments before first dose of study therapy, except: a. alopecia; b. hyperpigmentation;
• Willing to join in this study, able to provide written informed consent, good compliance and willing to cooperate with follow-up.

Exclusion Criteria:

• Has leptomeningeal metastasis or cystic metastatic lesions confirmed by MRI or lumbar puncture;
• Existence of third space fluid (e.g. massive ascites, pleural effusion, pericardial effusion) that is not well controlled by effective methods, e.g. drainage;
• Has CNS complications with the need for emergency intervention, or brain metastasis with poorly controlled symptoms by hormone or dehydration therapy, such as uncontrollable intracranial hypertension, mental disorder or epilepsy;

• Prior bevacizumab or EGFR-TKI is allowed, but should meet the following requirements at the same time:

  1. No disease progression during prior bevacizumab or EGFR-TKI;
  2. More than 3 months from the interruption of bevacizumab or EGFR-TKI to disease progression;
• Has received whole brain radiotherapy, chemotherapy, surgery within 2 weeks before first dose of study therapy; has received trastuzumab-based therapy or endocrine therapy within one week before first dose of study therapy; has received palliative radiotherapy for bone metastasis within 2 weeks before first dose of study therapy;
• Has known clinically significant lung disease, that is, moderate-to-severe lung disease which severely affects respiratory function, including but not limited to: idiopathic pulmonary fibrosis, pneumonitis. Prior ≥ grade 3 interstitial lung disease is not allowed to enrolment;
• Has received full-dose anticoagulants or thrombolytics within 10 days before enrolment, or non-steroid anti-inflammatory drugs with platelet inhibition (except low-dose aspirin (≤325mg qd) for preventive use);
• Existence of unhealed wound, active gastric ulcer, and other diseases which may cause haemorrhage risk (e.g., prior major operation within 4 weeks before enrolment, prior arterial or venous thrombotic event within one year before enrolment, prior cerebralvascular accident);
• Has known hereditary haemorrhagic tendency or coagulation disorder;
• Has joined in other clinical drug trials within 2 weeks before enrolment;
• Use of other antitumor systemic treatment during the study at the same time, except bisphosphonates for the treatment of bone metastasis or osteoporosis prevention;
• Other malignancy within prior 5 years unless curatively treated with no evidence of disease for at least recent 3 years, except: curatively treated in situ cancer of the cervix, skin basal cell carcinoma or skin squamous cell carcinoma;
• Cardiac insufficiency, including but not limited to: congestive heart failure, transmural myocardial infarction, angina which needs drug treatments, clinically significant valvulopathy and high-risk arrhythmia, or QTc abnormity with clinical significance in ECG examination during the screening period (corrected QTc >450 msec [male] or QTc >470 msec [female] under the resting state);
• Uncontrolled hypertension (under the resting state: systolic pressure >160mmHg or diastolic pressure >100mmHg);
• Other diseases which may affect study results, including but not limited to: 1) known history of immunodeficiency, including HIV-positive, other acquired or innate immunodeficient disease, or known history of organ transplantation; 2) HBsAg-positive and HBV DNA≥1000 IU/mL, or HCV antibody-positive, or treponema pallidum antibody-positive; 3) hypersensitivity to study therapy or any of its excipients; 4) severe infection requiring antibiotics, antiviral or antifungal treatment;
• Female patients during the gestation or suckling period, of childbearing potential and pregnancy test-positive, or unwilling to use an effective method of contraception during the whole study;
• Inability to swallow, intestinal obstruction or existence of other factors affecting medication and absorption;
• Any other conditions not appropriate for study enrolment in the opinion of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SHR-A1811+pyrotinib; In phase Ib, enrolled subjects will received SHR-A1811 combined with pyrotinib at different doses to confirm RP2D and evaluate the safety and tolerance.	Drug: SHR-A1811; ADC; Drug: Pyrotinib; anti-HER2 inhibitor
Experimental: SHR-A1811+pyrotinib+bevacizumab; In phase II, enrolled subjects will received SHR-A1811 combined with pyrotinib and bevacizumab to evaluate the efficacy and safety.	Drug: SHR-A1811; ADC; Drug: Pyrotinib; anti-HER2 inhibitor; Drug: Bevacizumab; bevacizumab biosimilar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RP2D in phase Ib	Recommended phase II dose confirmed by maximum tolerated dose (MTD) and tolerance of subjects.	From the enrolment of the first subject, to the end of Cycle 6 completion or disease progression or dose discontinuation due to AE in the last enrolled subject
CNS-ORR by investigator in phase II	CNS-ORR is the percentage of evaluable patients with a confirmed investigator-assessed CNS response of CR (complete response) or PR (partial response) per RANO-BM.	At baseline, at the time point of every 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicity (DLT) in phase Ib	Incidence of DLT	At the time point of 21 days from first medication
MTD in phase Ib	MTD is the highest dose that does not cause any adverse effects as follows: a) 1 subject experienced the treatment-related serious adverse effects that could endanger the life, cause permanent disability or death; b) 2 of 3 subjects experienced DLTs; c) 1 of the first 3 subjects experienced DLTs, and 1 of the additional 3 subjects at the same dose level experienced DLTs again.	From the enrolment of the first subject, to the end of Cycle 6 completion or disease progression or dose discontinuation due to AE in the last enrolled subject
Incidence and grade of adverse event (AE) and serious adverse event (SAE) in phase Ib	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. An SAE is defined as any medical event that results in any of the following outcomes: requires inpatient hospitalization or prolongation of existing hospitalization, disability or incapacity, affects ability to work, a life-threatening adverse event or death, a congenital anomaly.	From the time of informed consent provided to 3 months after the last dose of study therapy
CNS-ORR per RANO-BM in phase Ib	CNS-ORR is the percentage of evaluable patients with a confirmed CNS response of CR (complete response) or PR (partial response) per RANO-BM.	At baseline, at the time point of every 6 weeks
CNS-ORR per RECIST v1.1 in phase Ib	CNS-ORR is the percentage of evaluable patients with a confirmed CNS response of CR (complete response) or PR (partial response) per RECIST v1.1.	At baseline, at the time point of every 6 weeks
CNS-DCR in phase Ib	CNS-DCR is the percentage of evaluable patients with a confirmed CNS response of CR (complete response), PR (partial response) or SD (stable disease) per RECIST v1.1.	At baseline, at the time point of every 6 weeks
DoR in phase Ib	DoR is the time from the date of first detection of objective response (which is subsequently confirmed) until the date of objective radiographic disease progression.	up to 2 years
CNS-ORR per RECIST v1.1 in phase II	CNS-ORR is the percentage of evaluable patients with a confirmed CNS response of CR (complete response) or PR (partial response) per RECIST v1.1.	At baseline, at the time point of every 6 weeks
CNS-DCR in phase II	CNS-DCR is the percentage of evaluable patients with a confirmed CNS response of CR (complete response), PR (partial response) or SD (stable disease) per RECIST v1.1.	At baseline, at the time point of every 6 weeks
DoR in phase II	DoR is the time from the date of first detection of objective response (which is subsequently confirmed) until the date of objective radiographic disease progression.	up to 2 years
PFS in phase II	PFS is the time from the date of first dose until the date of objective radiographic disease progression or death (by any cause in the absence of progression).	up to 2 years
OS in phase II	OS is the time from the date of first dose until the date of death by any cause.	up to 2 years
Safety in phase II	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Percentage of participants who experienced an adverse event and discontinued study drug due to an AE.	From the time of informed consent provided to 30 days after the last dose of study therapy

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Hongxia Wang, Chief physician, Fudan University; Principal Investigator: Biyun Wang, Chief physician, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2025
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: November 20, 2024
• First Submitted That Met QC Criteria: December 2, 2024
• First Posted (Actual): December 5, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Skin Diseases; Breast Diseases; Nervous System Neoplasms; Central Nervous System Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: BCBM-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No