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). MedDRA version: 20.1 Level: PT Classification code 10055113 Term: Breast cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: LLT Classification code 10072740 Ter
Conditions
Interventions
Product Code: DS-8201a
Pharmaceutical Form: Powder for injection
INN or Proposed INN: Trastuzumab Deruxtecan
Other descriptive name: DS-8201A
Concentration unit: mg milligram(s)
Concentration type: eq
Sponsors
Medica Scientia Innovation Research S.L. (MEDSIR)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed Informed Consent Form (ICF) prior to participation in any study-related activities. 2. Male or female patients = 18 years at the time of signing ICF. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 for Cohorts 1 to 4 and 0-2 for cohort 5. 4. Life expectancy = 12 weeks. 5. Histologically confirmed invasive breast cancer based on local testing on the most recent analyzed biopsy of the following breast cancer (BC) subtypes per 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria: • Cohort 1 and 3: HER2 positive status • Cohort 4: HER2-low expressing status • Cohort 2 and 5: both HER2 positive and HER2-low expressing status 6. Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent. 7. At least one brain lesion needed to be measurable (=10 mm on T1-weighted, gadolinium-enhanced MRI) (study cohorts 2 to 4) or leptomeningeal carcinomatosis (LMC) with positive cerebrospinal fluid (CSF) cytology (study cohort 5). • Study cohort 1: History of BM that are non-progressing after WBRT and/or SRS and or surgery. • Study cohort 2: Presence of asymptomatic BM without clinical requirement for local intervention (WBRT and/or SRS and/or surgery). • Study cohorts 3 and 4: Evidence of new and/or progressive BM following previous WBRT and/or SRS and/or surgery. • Study cohort 5: Evidence of LMC with positive CSF cytology. 8. Previous treatments: • For HER2-positive patients have been previously treated with a taxane and at least one HER2-targeted therapy in the advanced scenario. • For HER2-low-expressing patients that also are endocrine receptor negative must have been previously treated with at least one chemotherapy regimen. If endocrine receptor positive, patients must have been previously treated with at least one chemotherapy and one endocrine regimen in the metastatic setting. 9. Patients must agree to collection of blood samples at the time of inclusion, at cycle 2 of treatment, and upon progression or study termination. Note: In study cohort 5: Patients must agree to perform spinal taps or must be willing to have an Ommaya reservoir placed for CSF assessment, at baseline, every three weeks for 12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks thereafter. 10. Willingness and ability to provide tumor biopsy (if feasible) from metastatic lesions or breast primary tumor both at the time of the inclusion and after disease progression in order to perform exploratory studies. 11. Patients should have left ventricular ejection fraction (LVEF) = 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrolment. 12. Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1. 13. Has adequate treatment washout period before enrollment, as indicated. 14. Major surgery: > 4 weeks; 15. Radiation therapy: > 4 weeks (palliative stereotactic radiation therapy to other areas = 2 weeks); 16. Anticancer systemic therapy (including immunotherapy, retinoid therapy, hormonal therapy): = 3 weeks (= 2 weeks or 5 half-lives, whichever is longer, for small-molecule targeted agents such as 5- fluorouracil-based agents, folinate agents, weekly paclitaxel; = 6 weeks for nitrosureas or mitomycin C); 17. Antibody based therapy: ³ 4 weeks; 18. Resoluti
Exclusion criteria
Exclusion criteria: 1. Inability to comply with study and follow-up procedures. 2. Previous treatment with trastuzumab deruxtecan (DS-8201a) or any other antibody drug conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase 1 inhibitor. 3. Medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction within 28 days prior to enrollment. 4. Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (males) based on average of the screening triplicate12- lead ECG. 5. History of (non-infectious) interstitial lung disease (ILD) that required steroids, has current ILD, or where suspected ILD cannot be ruled out by imaging at screening. 6. Clinically significant corneal disease in the opinion of the Investigator. 7. Spinal cord compression. 8. Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral breast cancer. 9. History of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product. 10. History of severe hypersensitivity reactions to other monoclonal antibodies. 11. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. 12. Patients with substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results. 13. Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Subjects should be tested for HIV prior to enrollment if required by local regulations or institutional review board (IRB)/ethics committee (EC). 14. Female patients who are pregnant or breastfeeding or planning to become pregnant. 15. No other systemic therapy for metastatic disease including chemotherapy, immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine therapy. 16. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 4 weeks of start of study drug, or patients who have not recovered from the side effects of any major surgery, or patients who may require major surgery during the study. 17. Radiotherapy within 4 weeks or limited-field palliative radiotherapy within 2 weeks prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade = 1 and/or from whom = 25% of the bone marrow has been previously irradiated. 18. Use of concurrent investigational agents or other concomitant anticancer therapies. 19. Use of intrathecal therapy for LMC 20. Active bleeding diathesis, previous history of bleeding diathesis, or chronic anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention). 21. Serious concomitant systemic disorder (e.g., active infection including HIV, active hepatitis, liver cirrhosis, end stage chronic renal disease) incompatible with the study (at the discretion of investigator). 22. Any of the following within 6 months of enrollment: severe/unstable angina, ongoing cardiac dysrhythmias of NCI-CTCAE v.5.0 grade 32, coronary/peripheral artery bypass graft, cerebrovascular a
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Cohort 1 • To assess efficacy -defined as 16 weeks progression-free survival (PFS)- 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.) Cohorts 2, 3, and 4 • To assess efficacy -defined as CNS ORR- of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic BC: a) HER2-positive or HER2-low expressing with untreated BMs (Cohort 2); b) HER2-positive with progressing BMs after local treatment (Cohort 3); c) HER2-low expressing with progressing BMs after local treatment (Cohort 4). Cohort 5 • 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 LMC.;Secondary Objective: Cohort 1 • To assess efficacy-defined as CNS ORR, CBR, time to response (TTR),duration of response (DoR), OS, 12-week CNS disease stabilization, and best percentage of change-of trastuzumab deruxtecan(DS-8201a) in this population. • To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population. Cohorts 2,3,and 4 • To assess efficacy-defined as 6-month PFS, CBR, TTR, DoR, OS, 12-week CNS disease stabilization, best percentage of change, and time to WBR and/or SRS (only for cohort 2)-of trastuzumab deruxtecan (DS-8201a) in study cohorts 2,3,and 4. • To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in study cohorts 2,3,and 4. Cohort 5 • To assess efficacy-defined as CNS ORR, CBR, TTR, DoR, PFS, OS, 12-week CNS disease stabilization, and best percentage of change-of trastuzumab deruxtecan(DS-8201a) in this population. • To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population.;Primary end point(s): Cohort 1 • 16 weeks-PFS, defined as the period of time from treatment initiation t | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Cohort 1: • CNS ORR, defined as a CR or PR, and determined locally by the investigator through the use of RANO-BM criteria. Cohort 5 • 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. Safety o Patient safety and 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. Cohort 2,3 and 4: Efficacy of 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 12 months. Progression will be determined locally by the investigator through the use of RANO-BM criteria (for CNS lesions) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria v.1.1 (in case of other lesions) o CNS ORR, defined as a CR or PR, and determined locally by the investigator through the use of RECIST criteria v.1.1. o CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, and determined locally by the investigator through the use of RANO-BM criteria (for CNS lesions) and RECIST criteria v.1.1 (in case of other lesions). o 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, and determined locally by the investigator through the use of RANO-BM criteria (for CNS lesions) and RECIST criteria v.1.1 (in case of other lesions). o 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, and determined locally by the investigator through use of RANO-BM criteria (for CNS lesions) and RECIST | — |
Countries
Spain
Contacts
Public ContactOperations Department
Medica Scientia Innovation Research S.L. (MEDSIR)
Outcome results
None listed