Phase II Study on Maintenance Therapy with Trastuzumab and Pertuzumab Post-Trastuzumab Deruxtecan in HER2-Positive Unresectable Metastatic Breast Cancer
- Trial ID
- 2023-507306-13-00
- Protocol
- MEDOPP562
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **progression-free survival (PFS)** rate at 1 year and the overall survival (OS) rate at 3 years in patients with **HER2-positive unresectable locally advanced or metastatic breast cancer** who have not received prior chemotherapy or HER2-targeted therapy for advanced disease. This is clinically relevant as it evaluates the efficacy of the induction treatment with Trastuzumab Deruxtecan (T-DXd) followed by PHESGO as maintenance therapy, potentially offering a new therapeutic strategy for this patient population.
Secondary objectives include:
- Assessing efficacy in terms of PFS, OS, objective response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DoR), and best percentage of change in tumor burden as per RECIST v.1.1.
- Evaluating changes in health-related quality-of-life (QoL) using the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30), Breast Cancer–Specific Quality of Life Questionnaire (QLQ-BR45), and the EuroQol 5-level EQ-5D version (EQ-5D-5L) questionnaire.
- Determining the safety and toxicity profile according to the NCI-CTCAE v.5.0.
- Identifying candidate biomarkers in tumor tissue and/or liquid biopsy that may correlate with biological responses, clinical benefit, and/or resistance.
- Determining the relationship between clinicopathological characteristics and prior treatment with efficacy endpoints.
- Determining the association of treatment efficacy outcomes with radiological imaging biomarkers.
Participants
The clinical trial involves participants diagnosed with **HER2-positive unresectable locally recurrent or metastatic breast cancer**. The study population includes both female and male subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate bone marrow, organ function, and a minimum life expectancy of 12 weeks at screening. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include individuals who have not received prior chemotherapy or HER2-targeted therapy for advanced disease, although one prior line of endocrine therapy is permissible. Participants may have undergone adjuvant or neoadjuvant chemotherapy and/or HER2-targeted therapy, provided there is a disease-free interval of at least 12 months from the completion of systemic treatment to metastatic diagnosis. Lifestyle considerations such as diet and physical activity are not specified. The trial requires participants to have a confirmed HER2-overexpressing tumor status and known estrogen receptor and progesterone receptor status. The sponsor has not disclosed specific lifestyle considerations or habits of the participants.
Plans and Procedures
The clinical trial is designed as a **Phase II**, open-label, single-arm study aimed at evaluating the maintenance therapy of **trastuzumab** and **pertuzumab** following induction treatment with **trastuzumab deruxtecan** in patients with **HER2-positive unresectable locally advanced or metastatic breast cancer**. The trial will assess the progression-free survival (PFS) rate at one year and the overall survival (OS) rate at three years. The study is expected to commence recruitment on April 1, 2024, and conclude by December 31, 2025, with a total duration of approximately 21 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including adequate bone marrow and organ function, and a minimum life expectancy of 12 weeks. Following the screening, eligible participants will receive the induction treatment with **trastuzumab deruxtecan** for a maximum period of six months. Subsequent to the induction phase, participants will transition to maintenance therapy with **Phesgo** (a combination of **trastuzumab** and **pertuzumab**) administered intravenously for up to 36 months.
Study visits will be scheduled regularly to monitor the participants' health status, treatment efficacy, and any adverse events. These visits will include assessments such as imaging studies to evaluate tumor response according to RECIST v.1.1 criteria, laboratory tests, and safety evaluations. The end-of-study visit will occur at the conclusion of the maintenance therapy or upon early termination from the study.
Participant involvement is expected to last up to 36 months, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The trial aims to provide valuable insights into the efficacy and safety of the maintenance therapy regimen in this patient population.
Treatment
The clinical trial involves the administration of **Phesgo 1200 mg/600 mg solution for injection**, which contains the active substances **trastuzumab** and **pertuzumab**. This pharmaceutical form is a solution for injection, administered via the **intravenous** route. The maximum daily dose is 1200 mg, with a total dose amounting to 1200 mg. The treatment period is set for a maximum of 36 months. This medication is utilized as a second-line treatment following the administration of **trastuzumab deruxtecan**. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
Another treatment used in the trial is **Phesgo 600 mg/600 mg solution for injection**, also containing **trastuzumab** and **pertuzumab**. This formulation is similarly administered intravenously. The maximum daily dose is 600 mg, with a total dose of 600 mg, and the treatment duration is up to 36 months. This product has been relabeled for clinical trial use and serves as a second-line treatment after **trastuzumab deruxtecan**. Compliance monitoring is conducted to ensure participants adhere to the prescribed dosing regimen.
The trial also includes the administration of **Enhertu 100 mg powder for concentrate for solution for infusion**, which contains the active substance **trastuzumab deruxtecan**. This medication is prepared as a solution for infusion and administered intravenously. The maximum daily dose is 5.4 mg/kg, with a total dose of 32.4 mg/kg, and the treatment period is limited to 6 months. **Trastuzumab deruxtecan** is used as a first-line treatment in this study. Participant compliance is closely monitored to ensure the correct dosing schedule is followed.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the 1-year **Progression-Free Survival (PFS)** rate, defined as the rate of patients without disease progression or death from any cause at one year after treatment initiation, and the 3-year **Overall Survival (OS)** rate, defined as the rate of patients alive three years after treatment initiation. These will be determined locally by the investigator using RECIST v.1.1 criteria.
Secondary endpoints encompass a range of efficacy measures: **PFS**, defined as the time from treatment initiation to the first occurrence of disease progression or death; **OS**, defined as the time from treatment initiation to death from any cause; **Objective Response Rate (ORR)**, defined as the rate of patients achieving complete or partial response; **Clinical Benefit Rate (CBR)**, defined as the rate of patients with objective response or stable disease for at least 24 weeks; **Time to Response (TTR)**, defined as the time from treatment initiation to the first objective tumor response; **Duration of Response (DoR)**, defined as the time from the first documented objective response to disease progression or death; and the best percentage of change from baseline in the size of target tumor lesions. These will also be determined using RECIST v.1.1 criteria.
Safety endpoints will be evaluated through changes from baseline in the EORTC QLQ-C30, EORTC QLQ-BR45, and EQ-5D-5L scales and symptom scores, as well as safety and tolerability assessments per NCI-CTCAE v.5.0. Exploratory endpoints will investigate the association of prognostic and predictive biomarkers with efficacy outcomes, as well as the efficacy endpoints according to different clinicopathological characteristics and prior treatment for early breast cancer. Additionally, the association of treatment efficacy outcomes with radiological imaging biomarkers will be explored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- No prior chemotherapy and/or HER2-targeted therapy for advanced disease (one prior line of endocrine therapy is allowed for MBC).
- 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.
- 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.
- 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).
- 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.
- 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.
- Participant must be accessible for treatment and follow-up.
- Female or male participants ≥ 18 years of age at the time of signing ICF.
- ECOG performance status of 0-1
- Minimum life expectancy of ≥ 12 weeks at screening.
- 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.
- Participants must have known estrogen receptor (ER) and progesterone receptor (PgR) status locally determined prior to Study entry.
- 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
- Evaluable disease according to RECIST v.1.1.
- 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.
Exclusion Criteria
- Participation in another clinical trial, interventional or observational, until the Study's safety visit. Note: participation in retrospective studies or data analysis is allowed.
- Treatment with approved or investigational cancer therapy within 14 days prior to initiation of Study drug.
- Has previously been treated with T-DXd in the adjuvant or neoadjuvant setting.
- 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).
- 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.
- Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances.
- 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.
- 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.
- 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.
- 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.
- 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.
- Pregnant or lactating women or participants not willing to apply highly effective contraception as defined in the protocol.
- 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.
- Has active primary immunodeficiency, known human immunodeficiency virus (HIV) infection.
- Other active uncontrolled infection at the time of enrollment.
- Receipt of live or attenuated vaccine within 30 days prior to the first dose of Study treatment.
- 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.
- Has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, contraindicate participant participation in the clinical Study.
- Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate participant participation.
- Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Apr 2024 | 12 |
 Germany | Not Recruiting | 01 Apr 2024 | 24 |
 Italy | Not Recruiting | 01 Apr 2024 | 16 |
 Spain | Not Recruiting | 01 Apr 2024 | 80 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Phesgo 600 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS | 600 | 36 | PRD8601831 |
Phesgo 1200 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS | 1200 | 36 | PRD8600161 |
Enhertu 100 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 5.4 | 6 | PRD8681525 |