Clinical trial NCT03870919: Locoregional Treatment and Palbociclib in de Novo, Treatment Naive, Stage IV ER+, HER2- Breast Cancer Patients
Official title: PALbociclib in Advanced Breast Cancer: Therapy INtegrating locorEgional Treatment and Palbociclib in de Novo, Treatment Naive, Stage IV ER+, HER2- Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Breast Cancer Stage IV
Radiotherapy
Surgery
Keywords: therapies combination
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2019-03-12
Enrollment: 200
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Approximately 3.5% to 6% of newly diagnosed breast cancer patients are stage IV metastatic. De novo metastatic breast cancer accounts for 20% to 25% of these cases. Despite a decrease in mortality in Europe and North America due to early detection and access to treatment, breast cancer remains the 2ⁿᵈ leading cause of cancer deaths in developed countries after lung cancer and the world's leading cause.

In the ESME French national retrospective cohort (NCT03275311), the newly diagnosed estrogen receptor (ER)-positive and HER2-negative (luminal) metastatic patients had a 59.1 months overall survival (OS) for pre-menopausal women and 44.7 months for postmenopausal women. In the same cohort, the median OS was 47.4 months for de novo metastatic patients with hormone receptor (HR)-positive / HER2-negative breast cancer.

The most important current treatment for metastatic breast cancer remains systemic therapy. Surgery and radiation are mainly used to treat symptoms. However, more than 15 retrospective studies have assessed the impact of locoregional treatment on relapse and OS. These studies suggested an improvement of the OS in patients with de novo metastatic breast cancer thanks to the addition of locoregional treatment to systemic therapy. Recent data from the ESME cohort suggest that patients with de novo luminal or HER2-positive metastatic breast cancer may benefit from local treatment of the primary tumor.

Several prospective trials have attempted to demonstrate the benefit of locoregional treatment with mixed results. This can be explained by a limited power of statistical analysis, on the recruitment of patients with breast cancer of all types, and on a limited access to effective systemic therapies in some cases and all before the area of anti CD4/6 which is the current standard treatment in patients with HR-positive / HER2-negative luminal metastatic disease.

However, guidelines indicate that a "multimodal approach, including curative locoregional treatments, should be considered". As a result, many clinicians offer locoregional treatment of the primary tumor, especially if there is a good response to the first line of systematic treatment.

Taken together, these data underscore the need for an evaluation of the value of combined therapy - endocrine therapy - CDK4/6 inhibitor and locoregional treatment - in this population of patients with newly diagnosed HR-positive / HER2-negative breast cancer.


Eligibility criteria: Inclusion Criteria:

1. Women with newly diagnosed and histologically proven de novo adenocarcinoma of the breast, Any T, any N, with at least one metastatic site measurable and/or non-measurable according to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 and/or PET Response Criteria in Solid Tumours (PERCIST) v1.0 and/or MD Anderson bone response criteria (MDA criteria). For patients with only bone metastases, at least one lytic and non-irradiated lesion must be present NB: Bilateral breast cancer is allowed only if tumours present similar histological criteria (morphological subtype, ER and HER2 status).
2. Estrogen Receptor (ER)-positive and HER2-negative breast cancer. To be considered as ER-positive, the biopsy of the primary tumour must display at least 10% of cancer cells with positive ER staining. HER2-positive is defined as IHC3+ or FISH/CISH amplified according to 2018 criteria
3. Age ≥18 years
4. Eastern Cooperative Oncology Group (ECOG) ≤2
5. Indication for treatment with palbociclib and letrozole (with or without ovarian suppression)
6. Diagnostic FFPE tumour sample and/or frozen primary breast tumour sample available
7. Women of childbearing potential must have a negative serum or urine pregnancy test done within 14 days before inclusion
8. Patients must agree to use adequate contraception methods for the duration of the study and for within 21 days after completing treatment
9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including absence of co-morbidities preventing surgery and or radiotherapy and any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Those conditions should be discussed with the patient before registration in the trial
10. Patient affiliated to a social security system
11. Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations

Exclusion Criteria:

1. Patients with advanced, symptomatic, visceral spread at a risk for short-term, life-threatening complications according to investigator judgement and at risk for visceral crisis as defined by ABC4\*
2. Women with previously diagnosed and treated ipsilateral adenocarcinoma of the breast
3. Women with previously treated or concomitant contralateral breast cancer except for Ductal carcinoma in situ (DCIS) treated with curative intent
4. Patients with another concomitant cancer
5. Concurrent enrolment in another clinical trial in which investigational therapies are administered or administration of an investigational drug within 30 days before inclusion
6. Pregnant women or women who are breast-feeding
7. Inability or willingness to swallow oral medication
8. HIV, hepatitis (B and C)
9. Active infection
10. Prior therapy for metastatic breast cancer (systemic or local)
11. Persons deprived of their freedom or under guardianship or incapable of giving consent

    * Visceral crisis is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since another treatment option at progression will probably not be possible.

Primary outcomes:
measure: Overall survival rate in patients receiving the letrozole plus palbociclib combination plus locoregional treatment
timeFrame: 24 months
Secondary outcomes:
measure: Clinical response rate on both primary tumour and metastasis disease
timeFrame: 24 months
measure: Pathological response rate in primary tumour
timeFrame: 26 weeks
measure: Conversion rate of breast surgery (conservative-radical)
timeFrame: 26 weeks
measure: Locoregional control rate
timeFrame: 60 months
measure: Progression-free survival (PFS)
timeFrame: 60 months
measure: Overall survival
timeFrame: 60 months
measure: Incidence of combined therapies in terms of adverse events
timeFrame: 60 months
measure: Registration of post letrozole-CDKi therapies
timeFrame: 60 months
measure: Evolution of quality of life during treatment
timeFrame: 60 months
measure: Evolution of quality of life during treatment
timeFrame: 60 months
measure: Evolution of quality of life during treatment
timeFrame: 60 months
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest-Site Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Caen
country: France
facility: Centre François Baclesse
city: Chalon-sur-Saône
country: France
facility: Hôpital privé sainte Marie
city: Cholet
country: France
facility: CH Cholet
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre George François Leclerc
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hôpital St Joseph
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: Hôpital saint Eloi CHU Montpellier
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Paris
country: France
facility: Institut Curie Site Paris
city: Paris
country: France
facility: Hôpital Saint Louis APHP
city: Paris
country: France
facility: Hôpital St Joseph
city: Paris
country: France
facility: Hôpital Tenon
city: Pau
country: France
facility: Centre Hospitalier de Pau
city: Pontoise
country: France
facility: CH René Dubos
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Saint Cloud
country: France
facility: Institut Curie Hôpital René Huguenin
city: Saint Gregoire
country: France
facility: Hôpital Privé à Saint Grégoire
city: Sarcelles
country: France
facility: GCS RISSA - Institut de cancérologie Paris Nord
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Institut Curie
name: Claire Bonneau, MD
role: PRINCIPAL_INVESTIGATOR
References: