Evaluation of Durvalumab and Genomic Analysis as Therapeutic Decision Tools in Metastatic Breast Cancer Patients

Trial ID: 2024-518002-41-00
Protocol: UC 0105/01304
Sponsor: Unicancer

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Diseases & Conditions

Breast cancer metastatic

Objectives

The primary objective of the SAFIR02-Breast trial is to evaluate whether treatment with **targeted agents** guided by high throughput molecular analyses, such as CGH array and next-generation sequencing, improves progression-free survival compared to maintenance chemotherapy in patients with **metastatic breast cancer**. This is assessed through a pooled analysis of the SAFIR02 Breast trial substudy 1 and a sample of patients from the SAFIR-PI3K trial. The clinical relevance of this objective lies in its potential to enhance therapeutic decision-making and improve patient outcomes by utilizing genomic data to tailor treatments.

Secondary objectives include:

Comparing progression-free survival in patients treated with the anti-PDL1 antibody, **durvalumab**, versus those receiving maintenance therapy in patients without actionable genomic alterations in the immune substudy 2.
In a pooled analysis of SAFIR02 Breast trial substudy 1 and a sample from the SAFIR-PI3K trial, comparing overall survival, evaluating overall response rates and changes in tumor size, and assessing safety.
In the immune substudy 2, comparing overall survival, evaluating overall response rates and changes in tumor size, and assessing safety.
Exploring the efficacy and safety of individual targeted agents in substudy 1, focusing on response rate, change in tumor size, progression-free survival, and overall survival.
Performing a prospective pooled analysis of SAFIR02 Lung and SAFIR02 Breast studies.
Correlating molecular characteristics in patients with efficacy endpoints, including response rate, progression-free survival, and overall survival, in each substudy.

Participants

The sponsor has not provided information regarding the total number of participants in this clinical trial. The study population consists of **women** aged 18 years and older, diagnosed with **metastatic breast cancer** and eligible for first or second-line chemotherapy. Participants are required to have a histologically proven diagnosis of breast cancer, with measurable target lesions or evaluable disease as per RECIST criteria v1.1. The trial includes individuals with a WHO Performance Status of 0 or 1, indicating they are in relatively good health despite their condition. The trial population was selected based on specific inclusion criteria, such as the absence of Her2 over-expression and the ability to provide biopsy samples, except in cases of bone metastases. Participants must have experienced metastatic relapse, progression, or stage IV disease at diagnosis. Lifestyle factors such as diet and physical activity are not specified, but participants must have social insurance coverage. The trial does not include male subjects, and the population is considered vulnerable due to the nature of the disease and treatment. Key inclusion criteria also consider the history of endocrine therapy in HR+ patients and the prior use of palbociclib for HR+/HER2- patients.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with **metastatic breast cancer**. This is a Phase II, randomized, double-blind, controlled trial. The primary objective is to assess whether treatment with targeted agents, guided by molecular analyses, improves progression-free survival compared to maintenance chemotherapy. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on April 7, 2014.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven breast cancer, measurable disease according to RECIST criteria, and the ability to provide informed consent. Follow-up visits will be scheduled to monitor treatment response and safety, with tumor assessments conducted using RECIST 1.1 criteria. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or withdrawal.

The expected length of participant involvement is contingent upon individual response to treatment, with the maximum treatment period set at 14 days per cycle. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial will also evaluate secondary endpoints such as overall survival and objective response, with safety assessments conducted according to NCI CTCAE v4.03 criteria.

Treatment

The clinical trial involves the administration of **IMFINZI** (durvalumab), a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, specifically designed for intravenous administration. The active substance, **durvalumab**, is a protein-based therapeutic agent, classified under the ATC code L01FF03. The concentration of the solution is 50 mg/mL, and the maximum daily dose is 10 mg/kg. The treatment is administered intravenously, with a maximum treatment period of 14 days. The product is manufactured by AstraZeneca AB and is not a pediatric formulation. The clinical batches used in this trial are intended for indications other than those previously authorized.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on evaluating the efficacy of durvalumab as a targeted agent guided by high throughput molecular analyses in patients with metastatic breast cancer. Participant compliance with the dosing schedule will be monitored to ensure adherence to the treatment protocol. The trial aims to assess the improvement in progression-free survival when using durvalumab compared to maintenance chemotherapy in the specified patient population.

Efficacy

Efficacy in the clinical trial titled "SAFIR02-Breast: Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic breast cancer" will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which is defined as the time from randomization to the first documented progression of disease or death from any cause. Tumor assessments for PFS will be conducted by investigators using RECIST 1.1 criteria. Patients who are alive at the time of analysis without documented progression will be censored at the last known alive date.

Secondary endpoints include Overall Survival (OS), which measures the time from randomization to death from any cause. Similar to PFS, patients who are alive at the time of analysis will be censored at the last known alive date. Additionally, Objective Response, defined as complete or partial response, will be evaluated using RECIST V1.1 criteria, with changes in tumor size over time being analyzed. Safety evaluations will be conducted according to NCI CTCAE v4.03 criteria.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Women (or men) with histologically proven breast cancer
Metastatic relapse or progression or stage IV at diagnosis
No Her2 over-expression
Patients with metastases (or primary tumour when locally advanced disease or stage IV at diagnosis) that can be biopsied, except bone metastases. In the case a fresh biopsy collection is not achievable, patients able to provide a FFPE biopsy sample of a metastasis (or primary tumour when locally advanced disease or stage IV at diagnosis) or FFPE cytoblock will be considered as well. ctDNA, ideally collected before chemotherapy initiation, will be a tertiary option in the following situation : existing tissue (fresh or FFPE) is not eligible for the study (i.e. <30% tumor cells, or insufficient size) AND patients cannot undergo a new biopsy (e.g. inaccessible location, or bone disease as the sole site, or patient real safety concerns).
Patients who are eligible for a first line of chemotherapy in metastatic setting (left to the discretion of investigators), or who are currently treated with a first line of chemotherapy with a maximum of 2 cycles at the time of biopsy.
For patients with HR+ disease, history of relapse or progression occurred during endocrine therapy, whatever the setting, or occurred less than 12 months after the end of endocrine therapy in adjuvant context
For HR+ / HER2- patients, should have received palbociclib if they are in the indication
Age ≥ 18 years.
WHO Performance Status 0/1.
Presence of measurable target lesion or evaluable disease according to RECIST criteria v1.1
Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
Patient with social insurance coverage

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Exclusion Criteria

Spinal cord compression and/or symptomatic or progressive brain metastases (unless asymptomatic or treated and stable without steroids during the last 30 days).
Patients with all target lesions in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them.
Patient who received more than 1 line of chemotherapy in metastatic setting at the time of the biopsy.
Patients who already had a genomic profile (both CGH and NGS analysis) in which no SAFIR02 targetable alterations have been identified (except for patients coming from SAFIR-TOR study).
Inability to swallow.
Major problem with intestinal absorption.
Any of the following cardiac criteria: - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG - Any factors increasing the risk of QTc prolongation or arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years old or any concomitant medication known to prolong the QT interval - Experience of any of the following procedures or conditions in the preceding 12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, past or current uncontrolled angina pectoris (Canadian Cardiovascular Society grade II-IV despite medical therapy), congestive heart failure NYHA Grade ≥2, torsades de pointes, current uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy), cardiomyopathy.
Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which requires steroïd treatment or any evidence of clinically interstitial lung disease.
Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin.
Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV) or any other serious active infection).
Previous history of myelodysplastic syndrome or acute myeloid leukaemia
Medical diagnosis of acne rosacea, severe psoriasis and severe atopic eczema.
Prior exposure to anthracyclines or mitoxantrone with cumulative exposure in excess of 360 mg/m² for doxorubicin, 720 mg/m² for epirubicin, or 72 mg/m² for mitoxantrone
Previous treatment with the same agent or in the same class as one of those used in the SAFIR02 trial (patients who received this previous targeted agent without the target prescreening are eligible but may not be eligible for randomisation in substudy 1 if the treatment allocated by the MTB is in the same class).
History of retinal degenerative disease, eye injury or corneal surgery in the previous 3 months, past history of central serous retinopathy or retinal vein occlusion, intraoccular pressure >21 mmHg, or uncontrolled glaucoma
Women who are pregnant.
History of heamorrhagic or thrombotic stroke, TIA or other CNS bleeds.
Renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome, renal tubular acidosis
Previous history of myelodysplastic syndrome or acute myeloid leukaemia
Patients using drugs that are known potent inhibitors or potent inducers or substrates of cytochrome P450 are not eligible if those treatments cannot be substituted during the randomized phase of the study
Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol including recent history (past 12 months) of drug abuse or alcohol abuse.
Individuals deprived of liberty or placed under the authority of a tutor.