Randomized, Open Label, Multicentric Phase III Trial to Evaluate the Safety and Efficacy of Palbociclib in Combination With HT Driven by ctDNA ESR1 Mutation Monitoring in ER+, HER2-negative Metastatic Breast Cancer Patients
Overview
- Phase
- Phase 3
- Intervention
- Palbociclib 125mg
- Conditions
- Metastatic Breast Cancer
- Sponsor
- UNICANCER
- Enrollment
- 1017
- Locations
- 82
- Primary Endpoint
- Progression-free survival (Step 2)
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
This study is a randomized, open-label, multicentric, phase III trial conducted in patients receiving aromatase inhibitor and palbociclib as first line therapy for estrogen receptor (ER)-positive HER2-negative metastatic breast cancer and which aims to evaluate, at the onset of ESR1 mutations in circulating tumor DNA, the efficacy of a change of the hormone therapy (aromatase inhibitor (AI) changed to fulvestrant) combined to palbociclib, together with the safety of hormone therapy and palbociclib combination in the overall population.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Women with proven loco-regionally recurrent or metastatic adenocarcinoma of the breast not amenable to curative therapy with disease considered potentially sensitive to aromatase inhibitors Note: patients relapsing while on adjuvant tamoxifen or other non-aromatase inhibitor adjuvant endocrine therapy and patients relapsing more than one year after the end of aromatase inhibitor adjuvant therapy are eligible for the present study;
- •Age ≥18 years;
- •Life expectancy \>3 months;
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
- •Estrogen Receptor (ER)-positive and HER2-negative breast cancer. Where available, assessment of Estrogen Receptor status should be based on the most recent tumor sample; to be considered as ER-positive, the most recent breast cancer tissue examined must display at least 10% of cancer cells with positive ER staining;
- •Tumor block (primary tumor or metastasis) available;
- •No prior systemic anti-cancer therapy for metastatic or advanced disease (chemotherapy, targeted therapy or hormone therapy); prior initiation of LHRH agonist or bone-directed agents is however allowed);
- •Menopausal patients or patients with suppressed ovarian function
- •Women with bilateral oophorectomy
- •Postmenopausal women, as defined by any of the following criteria:
Exclusion Criteria
- •Locally advanced breast cancer or loco-regional relapse amenable for any treatment with curative intent;
- •Her2-positive or equivocal tumor status either on the primary or on the recurrent tumor, defined as IHC3+, Fish/Cish amplified or Fish/Cish equivocal according to the ASCO2015 criteria;
- •Prior endocrine therapy in the metastatic setting is not allowed;
- •Prior treatment with any CDK 4/6 inhibitor in the adjuvant or metastatic setting (neoadjuvant/preoperative treatment is allowed); however, prior therapy with another targeted treatment in the adjuvant setting is allowed;
- •Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy;
- •Any major surgery (defined as requiring general anaesthesia) or significant traumatic injury within 4 weeks of treatment initiation or patients that may require major surgery during the course of the study; however, surgical diagnostic procedure is allowed (even if performed under general anaesthesia);
- •Known, active bleeding diathesis;
- •Any serious known concomitant systemic disorder (e.g. known active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed);
- •Patients unable to swallow tablets;
- •History of mal-absorption syndrome or other condition that would interfere with enteral absorption;
Arms & Interventions
B- Palbociclib + fulvestrant
After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with fulvestrant, a selective estrogen receptor down-regulator, 500 mg administered intramuscularly on Days 1, 15, and 29 and once monthly thereafter.
Intervention: Palbociclib 125mg
A- palbociclib + AI
After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme.
Intervention: Palbociclib 125mg
A- palbociclib + AI
After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme.
Intervention: Aromatase Inhibitors
B- Palbociclib + fulvestrant
After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with fulvestrant, a selective estrogen receptor down-regulator, 500 mg administered intramuscularly on Days 1, 15, and 29 and once monthly thereafter.
Intervention: Fulvestrant Injectable Product
Selection - Palbociclib + AI
All patients included into the study will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme
Intervention: Palbociclib 125mg
Selection - Palbociclib + AI
All patients included into the study will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme
Intervention: Aromatase Inhibitors
Outcomes
Primary Outcomes
Progression-free survival (Step 2)
Time Frame: From randomization to disease progression or death, up to 4 years
To assess whether a change of the hormone therapy associated with palbociclib will benefit patients for whom rising ESR1 mutations are detected during treatment with palbociclib and aromatase inhibitor. Progression-Free Survival (PFS) will be measured from the time of randomization to the time of tumor progression (as assessed by the investigator per RECIST v1.1) or death (whichever comes first) - in randomized patients.
Incidence of treatment-emergent Adverse Events
Time Frame: Throughout study completion, up to 4 years
Global safety of the combination of palbociclib + endocrine therapy in the whole population, with focus on hematological toxicities. Safety will be assessed by the collection of grade ≥3 adverse events, using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 - in all included patients.
Secondary Outcomes
- Progression-free survival (step 1&2)(From inclusion, up to 4 years)
- Progression-free survival (step 3)(From cross-over, up to 4 years)
- Time to strategy failure from randomization (Step 2 and 3)(From randomization, up to 4 years)
- Quality of life by quality of life questionnaire (QLQ)-C30(From inclusion and every 2 months until disease progression, up to 2 years)
- Chemotherapy-free survival (Step 2 and 3)(From randomization, up to 4 years)
- Incidence of treatment-emergent extra-hematological Adverse Events(Throughout study completion, up to 4 years)
- Other line of therapy(Throughout study completion, up to 4 years)
- Overall Survival(Throughout study completion, up to 4 years)