Neoplasms

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Nervous System Diseases

Breast Neoplasms

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Meningeal Carcinomatosis

Neoplasms, Second Primary

Brain Neoplasms

Breast Diseases

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Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Antineoplastic Agents

All Drugs and Chemicals

Trastuzumab

Trastuzumab deruxtecan

Hormones

Estrogens

Mitogens

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Antineoplastic Agents, Immunological

Immunoconjugates

Immunologic Factors

* Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);
* Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;
* Cohort 3: HER2-positive BC with progressing BMs after local treatment;
* Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;
* Cohort 5: HER2-positive or HER2-low expressing BC with LMC.

After having confirmed eligibility and entered into the clinical trial, patients will be treated with trastuzumab deruxtecan (DS-8201a) at 5.4 mg/Kg administered as an intravenous (IV) infusion on Day of 21-day cycle (Q3W), initially for at least 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes.

In patients with hormone receptor (HR)-positive status (estrogen receptor \[ER\] and/or progesterone receptor \[PgR\]) administration of endocrine therapy is not allowed.

In patients allocated in study cohort 5, administration of intrathecal therapy is not allowe

Marta Vaz Batista, MD

This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal Simon's design, phase II clinical trial

Pretreated, unresectable locally advanced or metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-positive or HER2-low expressing breast cancer (BC) with untreated or treated brain metastases (BMs) or leptomeningeal carcinomatosis (LMC).

This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal Simon's design, phase II clinical trial.

After confirmed eligibility, patients will be assigned to one of the following five study cohorts:

* Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);
* Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;
* Cohort 3: HER2-positive BC with progressing BMs after local treatment;
* Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;
* Cohort 5: HER2-positive or HER2-low expressing BC with LMC

DS-8201a for trEatment of aBc, BRain Mets, And Her2[+] Disease

Multicenter, Open-Label, Single-Arm, Multicohort Phase II Clinical Trial of Trastuzumab Deruxtecan(DS-8201a) in Human Epidermal Growth Factor Receptor 2 HER2+ Advanced Breast Cancer With Brain Metastases and/or Leptomeningeal Carcinomatosis

Overall change from baseline in patient-reported global health status/quality of life (GHS/QoL), functioning and symptoms; Time to deterioration in global QoL; Time to deterioration in pain; Time to next therapy.

Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical characteristics (e.g., baseline features) and outcome (e.g., duration of PFS).

To assess efficacy -defined as 16 weeks progression-free survival (PFS)- per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery). 16 weeks-PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first during at least first 6 months. Progression will be determined locally by the investigator through the use of Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria for intracranial (IC) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

To assess efficacy -defined as intracranial overall response rate (ORR-IC) per RANO-BM of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic BC:

1. HER2-positive or HER2-low expressing with untreated BMs (Cohort 2);
2. HER2-positive with progressing BMs after local treatment (Cohort 3);
3. HER2-low expressing with progressing BMs after local treatment (Cohort 4).

ORR-IC, defined as a complete response (CR) or partial response (PR), and determined locally by the investigator through the use of RANO-BM criteria.

To assess efficacy -defined as OS- of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-positive or HER2-low expressing BC with LMCOS defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up

ORR, defined as a complete response (CR) or partial response (PR), determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v. 1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

CBR, defined as an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

TTR, defined as the time from the treatment initiation to time of the first objective tumor response observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

OS, defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up.

PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

Best percentage of change from baseline in the size of CNS lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through use of RANO-BM criteria.

Patient safety and adverse events (AEs) will be evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. All AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the treatment.

PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

ORR, defined as a CR or PR, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

TTR, defined as the time from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

OS, defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up

Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

Time to WBR and/or SRS (only for cohort 2), defined as the time from the treatment initiation to time of CNS disease progression that requires treatment with WBR and/or SRS, and determined locally by the investigator through the use of RANO-BM criteria and RECIST criteria.

Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0. All AEs and SAEs will be assessed to determine the safety and tolerability of the treatment.

CNS ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

TTR, defined as the time from the treatment initiation to time of the first objective tumor response observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.

Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions

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