Trastuzumab; Pertuzumab for HER2-positive unresectable locally advanced or metastatic breast cancer | HER2-positive unresectable locally recurrent or metastatic breast cancer

Inclusion criteria

• {"criterion_text":"- Participants must be capable to understand the purpose of the Study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.\n- ECOG performance status of 0-1\n- Minimum life expectancy of ≥ 12 weeks at screening.\n- Evidence of HER2-overexpressing tumor status as per 2018 American Association of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 guidelines and confirmed by any MEDSIR’s designated central lab (Europe) or participant has a pathology report confirming HER2- overexpression by local testing (Unites States), on the most recent available metastatic sample. Analysis of the primary tumor sample will be accepted if the metastatic tissue is inaccessible and should be consulted with the MM in all cases. Note: In Europe sites, tumor tissue must be sent to MEDSIR’s designated central lab for confirmation of HER2 status.\n- Participants must have known estrogen receptor (ER) and progesterone receptor (PgR) status locally determined prior to Study entry.\n- Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to treatment with curative intent\n- Evaluable disease according to RECIST v.1.1.\n- Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue sample at the time of the inclusion. If archival tissue is not available, a newly obtained baseline biopsy of an accessible tumor lesion is required prior to start of Study treatment.\n- No prior chemotherapy and/or HER2-targeted therapy for advanced disease (one prior line of endocrine therapy is allowed for MBC).\n- Participants may have received adjuvant or neoadjuvant chemotherapy and/or HER2-targeted therapy before study treatment initiation, with a DFI from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of at least 12 months.\n- Participants with adequate bone marrow and organ function: a. Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first Study treatment dose): White blood cell (WBC) count > 3.0 x 109 /L, absolute neutrophil count (ANC) ≥ 1.5 x 109 /L, platelet count ≥ 100.0 x109 /L, and hemoglobin ≥ 9.0 g/dL. b. Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (≤ 3 x ULN in participants with known history of Gilbert’s disease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 × ULN in participants with liver and/or bone metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x ULN (≤ 3 x ULN in participants with liver metastases). c. Renal: Creatinine clearance ≥ 50 mL/min as determined by Cockcroft Gault (using actual body weight). d. Coagulation: International normalized ratio or prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.\n- Resolution of all acute toxic effects of prior anticancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the participants at investigator's discretion).\n- Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before Study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of Study treatments. Female participants must refrain from egg cell donation and breastfeeding during this same period.\n- Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last dose of T-DXd or 7 months after the last dose of PHESGO to prevent pregnancy. Male participants must not donate or bank sperm during this same period. Not engaging in heterosexual activity (sexual abstinence) for the duration of the Study and drug washout period is an acceptable practice if this is the preferred usual lifestyle of the participant.\n- Participant must be accessible for treatment and follow-up.\n- Female or male participants ≥ 18 years of age at the time of signing ICF."}

Exclusion criteria

• {"criterion_text":"- Participation in another clinical trial, interventional or observational, until the Study's safety visit. Note: participation in retrospective studies or data analysis is allowed.\n- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within three months of the Study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.\n- Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.\n- Pregnant or lactating women or participants not willing to apply highly effective contraception as defined in the protocol.\n- Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.\n- Has active primary immunodeficiency, known human immunodeficiency virus (HIV) infection.\n- Other active uncontrolled infection at the time of enrollment.\n- Receipt of live or attenuated vaccine within 30 days prior to the first dose of Study treatment.\n- A history of uncontrolled seizures, CNS disorders, or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to Study drugs or interfering with participant safety.\n- Has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, contraindicate participant participation in the clinical Study.\n- Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate participant participation.\n- Treatment with approved or investigational cancer therapy within 14 days prior to initiation of Study drug.\n- Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.\n- Has previously been treated with T-DXd in the adjuvant or neoadjuvant setting.\n- Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Note I: Participants with a history of CNS metastases are eligible if they have been previously treated with local therapy, are clinically stable, and off anticonvulsants and steroids for at least 14 days before the first dose of Study treatment. Note II: Participants with clinically inactive (asymptomatic) brain metastases may be included in the study after consultation with the Study’s medical monitor (MM).\n- Has a concurrent malignancy or malignancy within 5 years of Study enrollment with the exception of carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor’s MM is required.\n- Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances.\n- Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks prior to start of Study treatment.\n- Major surgical procedure or significant traumatic injury within 14 days before the first dose of Study treatment or anticipation of need for major surgery within the course of the Study treatment.\n- Has an active cardiac disease or a history of cardiac dysfunction or severe conduction abnormalities including, but not confined, to any of the following: a. Unstable angina pectoris, documented myocardial infarction, or symptomatic cardiac heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) within six months prior to Study entry. Poorly controlled hypertension (i.e., systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg). c. Symptomatic pericarditis. d. Left ventricular ejection fraction (LVEF) < 55% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO). e. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia), which is symptomatic or requires treatment (NCI-CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, asymptomatic sustained ventricular tachycardia, or higher-grade atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz 2] or thirddegree AV-block). Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers will be permitted to enroll. f. QT Interval Corrected by Fridericia’s formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead ECG. g. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. h. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives."}

Primary endpoints

• {"endpoint_text":"- 1-year PFS rate, defined as the rate of participants with absence of disease progression or death from any cause 1 year after t treatment initiation, as determined locally by the investigator using RECIST v.1.1 criteria.","definition_or_measurement_approach":"Defined as the rate of participants with absence of disease progression or death from any cause 1 year after treatment initiation, as determined locally by the investigator using RECIST v.1.1 criteria."}
• {"endpoint_text":"- 3-year OS rate, defined as the rate of participants alive 3 years after treatment initiation, as determined locally by the investigator.","definition_or_measurement_approach":"Defined as the rate of participants alive 3 years after treatment initiation, as determined locally by the investigator."}

Secondary endpoints

• {"endpoint_text":"- PFS, defined as the period from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Period from treatment initiation to first occurrence of disease progression or death, determined locally by investigator using RECIST v1.1."}
• {"endpoint_text":"- OS, defined as the period from treatment initiation to death from any cause, as determined locally by the investigator.","definition_or_measurement_approach":"Period from treatment initiation to death from any cause, determined locally by investigator."}
• {"endpoint_text":"- ORR, defined as the rate of participants with complete response (CR) or partial response (PR), as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Rate of participants with CR or PR per RECIST v1.1 determined locally."}
• {"endpoint_text":"- CBR, defined as the rate of participants with objective response (CR or PR), or stable disease for at least 24 weeks, as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Rate of participants with CR/PR or stable disease ≥24 weeks per RECIST v1.1 determined locally."}
• {"endpoint_text":"- TTR, defined as the period from treatment initiation to the first objective tumor response (tumor shrinkage of ≥ 30%) observed for participants who achieved a CR or PR, as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Period from treatment initiation to first objective tumor response (≥30% shrinkage) per RECIST v1.1 determined locally."}
• {"endpoint_text":"- DoR, defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Period from first documented response to progression or death per RECIST v1.1 determined locally."}
• {"endpoint_text":"- Best percentage of change from baseline in the size of target tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Maximum percent change from baseline in target lesions per RECIST v1.1 determined locally."}
• {"endpoint_text":"- Safety endpoints: Changes from baseline in the EORTC QLQ-C30, the EORTC QLQ-BR45, and the EQ-5D-5L scales and symptoms scores.","definition_or_measurement_approach":"Changes from baseline in QoL scores using EORTC QLQ-C30, QLQ-BR45, and EQ-5D-5L instruments."}
• {"endpoint_text":"- Safety endpoints: Safety and tolerability as per NCI-CTCAE v.5.0.","definition_or_measurement_approach":"Adverse events graded per NCI-CTCAE v5.0."}
• {"endpoint_text":"- Exploratory endpoints: Association of prognostic and/or predictive biomarkers in tumor tissue and/or liquid biopsy with PFS, OS, ORR, CBR, TTR, DoR, and maximum tumor reduction.","definition_or_measurement_approach":"Correlative analyses of biomarkers (gene/protein expression, ctDNA, mutational profiling) vs efficacy endpoints."}
• {"endpoint_text":"- Exploratory endpoints: Efficacy endpoints for all participants according to different clinicopathological characteristics and prior treatment for early breast cancer.","definition_or_measurement_approach":"Subgroup analyses by clinicopathological characteristics and prior early breast cancer treatment."}
• {"endpoint_text":"- Exploratory endpoints: Association of treatment efficacy outcomes in all participants with radiological imaging biomarkers.","definition_or_measurement_approach":"Association analyses between imaging biomarkers and efficacy outcomes."}

Other endpoints

• {"endpoint_text":"- Exploratory endpoints: Association of prognostic and/or predictive biomarkers in tumor tissue and/or liquid biopsy with PFS, OS, ORR, CBR, TTR, DoR, and maximum tumor reduction.\n- Exploratory endpoints: Efficacy endpoints for all participants according to different clinicopathological characteristics and prior treatment for early breast cancer.\n- Exploratory endpoints: Association of treatment efficacy outcomes in all participants with radiological imaging biomarkers.","definition_or_measurement_approach":"Exploratory biomarker and imaging correlation analyses as described in the protocol (tumor tissue and/or liquid biopsy; clinicopathological subgroup analyses; imaging biomarkers association)."}

Germany

Earliest CTIS Part Ii Submission Date

22-04-2024

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

694

Number Of Sites

5

Number Of Participants

24

France

Earliest CTIS Part Ii Submission Date

17-04-2024

Latest Decision Or Authorization Date

13-03-2026

Processing Time Days

695

Number Of Sites

3

Number Of Participants

12

Italy

Earliest CTIS Part Ii Submission Date

20-02-2024

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

756

Number Of Sites

5

Number Of Participants

16

Spain

Earliest CTIS Part Ii Submission Date

15-03-2024

Latest Decision Or Authorization Date

25-03-2026

Processing Time Days

740

Number Of Sites

24

Number Of Participants

80

Primary sponsor

Full Name

Medica Scientia Innovation Research S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain

Third parties

• {"country":"Spain","full_name":"Hospital Universitario Ramon Y Cajal","duties_or_roles":"Biobank","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Croatia","full_name":"Optimapharm d.o.o.","duties_or_roles":"Sponsor duties codes present: 1, 12, 15 (15 described as 'contract negotiations')","organisation_type":"Pharmaceutical company"}