A Multi-cohort Phase II Study of HER2-positive and Triple-negative Breast Cancer Brain Metastases.

Study Overview
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Brief Summary
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The study is being conducted to assess the effectiveness and safety of treatment options for breast cancer brain metastases based on molecular typing.

Detailed Description
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This is a prospective, single-arm, single-center, two cohorts, Simon's two-stage design, phase II clinical trial in HER2-positive and triple-negative breast cancer brain metastases patients. Subjects will be divided into two cohorts by hormone receptor status and HER2 status. HER2+/HR- subjects will enter Cohort A to receive pyrotinib plus temozolomide; HER2-/HR- subjects will enter Cohort B to receive bevacizumab, SHR1316 combined with cisplatin/carboplatin. Subjects in both cohorts will be treated until disease progression, toxicity is intolerable, informed consent is withdrawn, and investigators determine that medication must be discontinued. Drug efficacy and safety data will be collected.

Official Title
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A Prospective, Single-arm, Single-center, Multi-cohort Phase II Clinical Study of HER2-positive and Triple-negative Breast Cancer Brain Metastases

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Pyrotinib
* Drug: Temozolomide Injection
* Drug: SHR-1316
* Drug: Bevacizumab
* Drug: Cisplatin/Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old, and ≤ 70 years old, both genders; ECOG performance status 0-2; Pathological tests confirm HR-negative / HER2-positive or HR-negative / HER2-negative breast cancer；there is evidence of local recurrence or metastasis；not suitable with curative surgery or radiation therapy；HR negative is defined as: ER-negative and PR-negative, the proportion of positively stained tumor cells in all tumor cells is <1%；HER2-positive is defined as: Immunohistochemical detection of HER2 (3+) or fluorescence in situ hybridization (FISH) detection result is positive; Patients with HER2 + breast cancer who have previously received trastuzumab and taxanes; For TNBC, it is required that no platinum drugs have been used before, or platinum drugs have been used (cisplatin/carboplatin only one regimen) and platinum sensitive: no progression during at least 4 cycles of treatment, more than 3 month period between last platinum regimen and the progression of disease； MRI confirmed brain metastases, at least one intracranial parenchymal metastatic lesion with a longest diameter ≥ 1.0 cm without prior radiotherapy； Mannitol or steroid hormone therapy is allowed before enrollment, but the dose of steroid hormone should be stable for at least one week; Adequate function of major organs meets the following requirements: (1)Blood routine ANC≥1.5×109/L； PLT≥75×109/L； Hb≥90 g/L(Allows blood transfusion or the use of medication to ensure that the content of hemoglobin) (2)Coagulation: INR≤1.5，APTT≤1.5×ULN, PT does not exceed the upper limit of normal (3)Blood biochemistry TBIL≤1.5 × ULN; ALT and AST≤3 × ULN (liver metastasis≤5.0 × ULN); Urea nitrogen ≤ 1.5 × ULN; Cr≤1.5 × ULN or creatinine clearance ≥50 mL / min (Cockcroft-Gault formula) (4)Cardiac ultrasound: LVEF≥50%; (5)12-lead ECG: females QTcF interval <470msec and males <450ms; 8.Willing to join the study, sign informed consent, have good compliance and cooperate with follow-up. Exclusion Criteria: Leptomeningeal or cystic metastases confirmed by MRI or lumbar puncture. Presence of third interstitial fluid that cannot be controlled by drainage or other methods (e.g., a large amount of pleural effusion and ascites); Suffering from gastrointestinal diseases such as intestinal obstruction, peptic ulcer or active bleeding, which affects the taking and absorption of drugs; Whole brain radiotherapy, chemotherapy or surgery within 14 days prior to enrollment. Has received prior therapy with trastuzumab within the previous week； Subjects with HR+/HER2- who has received prior therapy with temozolomide. Subjects with HR-/HER2- who has received prior therapy with bevacizumab or PD-1/PD-L1； Any previous or concurrent treatment with Anti-HER2 TKIs； Participation in any other clinical trials within 2 weeks of enrollment； Concurrent use of any other Anti-cancer drugs； Other malignancies within 5 years, except cured in-situ of uterine cervix carcinoma , skin basal cell carcinoma and squamous-cell carcinoma； History of heart disease: (1) Arrhythmias requiring medical treatment or clinical significance, (2) Myocardial infarction, (3) Heart failure, (4)Any heart diseases that investigator believes not suitable for this study; History of allergy or hypersensitivity to any of the study drugs or study drug components； History of immunodeficiency including HIV-positive, active hepatitis B/C, other acquired, congenital immunodeficiency disease or history of organ transplantation； A clear history of neurological or mental disorders, including epilepsy or dementia； Pregnant or breastfeeding women. Women of childbearing potential who have a positive pregnancy test or unwilling to use adequate contraception prior to enrollment and for the duration of study participation； According to the investigator's judgment, there is a concomitant disease that seriously endangers the safety of subjects or affects the completion of the study (including but not limited to severe hypertension, severe diabetes, active infection, thyroid disease that cannot be controlled by drugs)； Any condition which in the investigator's opinion makes the subjects unsuitable for the study participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort HR+/HER2+<br>Hormone receptor negative, HER2 positive participants will receive Pyrotinib in combination with Temozolomide until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first. | Drug: Pyrotinib<br>* PO<br>* Other names: SHR-1258;Drug: Temozolomide Injection<br>* IV<br>* Other names: Ainituo;|
| Experimental: Cohort HR-/HER2-<br>Hormone receptor negative, HER2 negative participants will receive SHR1316 in combination with bevacizumab plus cisplatin or carboplatin until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first. | Drug: SHR-1316<br>* IV<br>* Other names: HTI-1088;Drug: Bevacizumab<br>* IV<br>* Other names: Avastin;Drug: Cisplatin/Carboplatin<br>* IV<br>* Other names: Bobei;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate in the CNS | CNS ORR will be assessed by the investigator according to RANO-BM criteria. According to these criteria Complete Response (CR) will be defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions, no corticosteroids; stable or improved clinically. Partial Response (PR) will be defined as a decrease of at least 30% in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD, sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. | from enrollment to progression or death (for any reason), assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate in the CNS | CNS clinical benefit rate (CBR) will be defined as the percentage of patients who experience a CR, PR or Stable Disease (SD) for at least 24 weeks. | from enrollment to progression or death (for any reason), assessed up to 24 months | 
| Progression-free survival | PFS will be defined as the time from the first dose of treatment to death or disease progression. | Up to 2 years | 
| Overall survival | OS will be defined as the time from the first dose of treatment to death for any cause. | Up to 2 years | 
| First progression site | The first lesion to progress. | Up to 2 years | 
| Safety as assessed by percentage of patients with any Adverse Event | Adverse event according to NCI-CTC AE 5.0 | Up to 2 years |