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

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

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

Study Overview

• Status: Unknown
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Bevacizumab; Drug: Pyrotinib; Drug: Temozolomide Injection; Drug: SHR-1316; Drug: Cisplatin/Carboplatin

Detailed Description

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 Subjects in both cohorts will be treated until disease progression, toxicity is intolerable, informed consent is withdrawn, and investigators determine that medication must be discontinued.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.

• Study Type: Interventional
• Enrollment (Anticipated): 59
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhang Jian; Phone Number: 13918273761; Email: syner2000@163.com
• Study Contact Backup: Name: Li Ting; Phone Number: 13917792964

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years old, and ≤ 70 years old, both genders;
2. ECOG performance status 0-2;
3. 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;
4. 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；
5. MRI confirmed brain metastases, at least one intracranial parenchymal metastatic lesion with a longest diameter ≥ 1.0 cm without prior radiotherapy；
6. Mannitol or steroid hormone therapy is allowed before enrollment, but the dose of steroid hormone should be stable for at least one week;
7. 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:

1. Leptomeningeal or cystic metastases confirmed by MRI or lumbar puncture.
2. Presence of third interstitial fluid that cannot be controlled by drainage or other methods (e.g., a large amount of pleural effusion and ascites);
3. Suffering from gastrointestinal diseases such as intestinal obstruction, peptic ulcer or active bleeding, which affects the taking and absorption of drugs;
4. Whole brain radiotherapy, chemotherapy or surgery within 14 days prior to enrollment. Has received prior therapy with trastuzumab within the previous week；
5. 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；
6. Any previous or concurrent treatment with Anti-HER2 TKIs；
7. Participation in any other clinical trials within 2 weeks of enrollment；
8. Concurrent use of any other Anti-cancer drugs；
9. Other malignancies within 5 years, except cured in-situ of uterine cervix carcinoma , skin basal cell carcinoma and squamous-cell carcinoma；
10. 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;
11. History of allergy or hypersensitivity to any of the study drugs or study drug components；
12. History of immunodeficiency including HIV-positive, active hepatitis B/C, other acquired, congenital immunodeficiency disease or history of organ transplantation；
13. A clear history of neurological or mental disorders, including epilepsy or dementia；
14. 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；
15. 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)；
16. Any condition which in the investigator's opinion makes the subjects unsuitable for the study participation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort HR+/HER2+; 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; PO; Other Names: SHR-1258; Drug: Temozolomide Injection; IV; Other Names: Ainituo
Experimental: Cohort HR-/HER2-; 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: Bevacizumab; IV; Other Names: Avastin; Drug: SHR-1316; IV; Other Names: HTI-1088; Drug: Cisplatin/Carboplatin; IV; Other Names: Bobei

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Study Director: Jian Zhang,MD, Fudan University

Study record dates

Study Major Dates

• Study Start (Anticipated): March 30, 2020
• Primary Completion (Anticipated): December 30, 2021
• Study Completion (Anticipated): January 30, 2022

Study Registration Dates

• First Submitted: February 24, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (Actual): March 11, 2020

Study Record Updates

• Last Update Posted (Actual): March 11, 2020
• Last Update Submitted That Met QC Criteria: March 9, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Brain Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Cisplatin; Temozolomide; Bevacizumab
• Other Study ID Numbers: HR-BLTN 015

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No