Evaluation of Palbociclib Combined with Endocrine Therapy in ER+/HER2- Metastatic Breast Cancer Using Circulating DNA ESR1 Mutation Monitoring
- Trial ID
- 2024-510704-37-00
- Protocol
- UC-0140/1615
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the global **safety** of the combination of palbociclib and endocrine therapy in patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. This includes assessing the potential sequential administration of fulvestrant plus palbociclib, with a particular focus on hematological toxicities. Additionally, the study aims to determine whether an early switch from an aromatase inhibitor with palbociclib to fulvestrant with palbociclib, following the detection of circulating tumor DNA (ctDNA) indicating rising ESR1 mutations, provides clinical benefit to patients. This is clinically relevant as it may inform treatment strategies to improve patient outcomes by potentially delaying disease progression and managing treatment-related toxicities.
Secondary objectives include:
- Assessing progression-free survival (PFS) in patients undergoing a cross-over following RECIST tumor progression in Arm A.
- Reporting the efficacy of palbociclib combined with hormone therapy from the date of initial inclusion into the trial.
- Evaluating whether an early switch to fulvestrant leads to a longer time to strategy failure and chemotherapy-free survival in patients with rising ESR1 mutations.
- Obtaining additional safety data in a broad patient population treated with palbociclib and hormone therapy.
- Studying the patient's reported quality of life before and until two years of therapy.
- Reporting the anti-cancer treatments received after the first-line therapy and the overall survival of included patients.
- Conducting quantitative and qualitative analyses of circulating tumor DNA detection before and during therapy, comparing with archived tumor tissue, clinical/pathological characteristics, and therapy efficacy.
Participants
The clinical trial focuses on a population of **women** diagnosed with **ER+/HER2- metastatic breast cancer**. The study includes participants aged 18 years and older, with no upper age limit specified. The trial exclusively involves female subjects, and the sponsor has not provided the total number of participants. Participants were selected based on their diagnosis of estrogen receptor-positive and HER2-negative breast cancer, with a requirement for adequate organ and marrow function. The trial population includes women with loco-regionally recurrent or metastatic adenocarcinoma of the breast, not amenable to curative therapy, and potentially sensitive to aromatase inhibitors. Participants must have a life expectancy greater than three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study does not include male subjects, and it involves a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the provided data.
Plans and Procedures
The clinical trial is a **randomized**, open-label, multicentric phase III study designed to evaluate the safety and efficacy of **palbociclib** in combination with hormone therapy in patients with **estrogen receptor-positive, HER2-negative metastatic breast cancer**. The trial aims to assess the global safety of the combination of palbociclib and endocrine therapy, with a particular focus on hematological toxicities. The study also investigates whether an early switch from an aromatase inhibitor to **fulvestrant** in combination with palbociclib, following the detection of rising ESR1 mutations, benefits patients. The trial is expected to conclude by June 2025, with recruitment having started in March 2017.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate organ function, life expectancy, and performance status. Following inclusion, participants will be randomized and receive treatment according to the study protocol. Regular follow-up visits will be conducted to monitor safety, efficacy, and any adverse events, with assessments including laboratory tests and imaging studies as per RECIST v1.1 criteria. The end-of-study visit will occur upon completion of the treatment period or earlier if the participant experiences disease progression or unacceptable toxicity.
The expected length of participant involvement is determined by the progression-free survival endpoint, measured from randomization to tumor progression or death. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial's primary endpoints include progression-free survival and safety, while secondary endpoints encompass overall survival, chemotherapy-free survival, and quality of life assessments. The study will also explore translational endpoints, such as circulating tumor DNA detection at various time points.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Letrozole** is provided in the form of a tablet, with a maximum daily dose of 2.5 mg and a total dose of up to 70 mg over a 28-day treatment period. The route of administration is oral. **Letrozole** is a chemical substance used in the trial to evaluate its efficacy and safety in combination with other treatments.
**Exemestane** is also administered as a tablet, with a maximum daily dose of 25 mg and a total dose of up to 700 mg over the same 28-day period. This medication is taken orally and is a chemical compound being tested for its potential benefits in the study.
**Anastrozole** is another tablet-form medication used in the trial, with a maximum daily dose of 1 mg and a total dose of 28 mg over 28 days. It is administered orally and is included in the study to assess its role in combination therapies.
**Palbociclib** is provided in a hard capsule form, with a maximum daily dose of 125 mg and a total dose of 2625 mg over the 28-day treatment period. This medication is taken orally and is a chemical substance being evaluated for its effectiveness in combination with hormone therapies.
**Fulvestrant** is administered as a solution for injection, with a maximum daily dose of 500 mg and a total dose of 1000 mg over 28 days. This chemical compound is delivered via infusion and is included in the trial to assess its potential benefits when used in combination with other treatments.
Throughout the study, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to evaluate the safety and efficacy of these medications, particularly focusing on hematological toxicities and the potential benefits of switching hormone therapies based on circulating DNA ESR1 mutation monitoring.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, which will be measured from the time of randomization following the detection of rising ESR1 mutations to the time of tumor progression or death, whichever occurs first. This assessment will be conducted in randomized patients, utilizing the investigator's tumor assessments as the primary data source, in accordance with RECIST v1.1 criteria. Additionally, safety will be evaluated by collecting data on grade ≥3 adverse events, focusing on hematological toxicities, using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
Secondary endpoints include measuring PFS from the time of cross-over and from the time of inclusion to tumor progression or death, as well as time to strategy failure, chemotherapy-free survival, and overall survival. Quality of life will be assessed using the QLQ-C30 questionnaire at baseline, randomization, and every two cycles until disease progression or up to two years post-inclusion. Translational endpoints will involve ctDNA detection at various time points. These efficacy parameters will be collected and analyzed throughout the study duration, with specific timepoints and methods outlined in the trial protocol.
Inclusion and Exclusion Criteria
Inclusion Criteria
- STEP1 : Women with proven loco-regionally recurrent or metastatic disease adenocarcinoma of the breast not amenable to curative therapy with disease considered potentially sensitive to aromatase inhibitor
- STEP 1 : Age ≥18 years;
- STEP 1 : Life expectancy > 3 months;
- STEP 1 : Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
- STEP 1 : Estrogen Receptor-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 ERpositive, the most recent breast cancer tissue examined must display at least 10% of cancer cells with positive ER staining;
- STEP 1 : Tumor block (primary tumor or metastasis) available;
- STEP 1 : 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);
- STEP 1 : Menopausal patients or patients with suppressed ovarian function
- STEP 1 : Patients may have measurable (according to Response Evaluation Criterion in Solid Tumors (RECIST v1.1) or not measurable disease
- STEP 1 : Adequate organ and marrow function as defined : Hemoglobin ≥ 90 g/L; Absolute neutrophil count ≥ 1.5 G/L; Platelet count ≥ 100 G/L; Serum bilirubin ≤ 1.5 × ULN. This will not apply to patients with confirmed Gilbert’s syndrome; ALT and AST ≤ 3 × ULN; Alkaline phosphatase ≤ 2.5× ULN; Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 60 mL/min as determined by Cockcroft-Gault (using actual body weight) formula for females [creatinine clearance =Weight (kg) × (140 - Age) × 0.85 (mL/min)/ (72 × serum creatinine (mg/dL))
- STEP 1 : Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including screening evaluations;
- STEP 1 : Resolution of all acute toxic effects or prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 4.03 grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion);
- STEP 1 : Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations;
- STEP 1 : Patient affiliated to a social security system.
- STEP 2 : Patients included and treated within the PADA-1 protocol, who received a combination of aromatase inhibitor and palbociclib;
- STEP 2 : Detection of a rise in circulating ESR1 mutation as defined in the protocol;
- STEP 2 : Absence of concomitant RECIST 1.1 proven tumor progression;
- STEP 2 : Life expectancy > 3 months;
- STEP 2 : Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
- STEP 2 : Patients who have been properly informed and have signed the informed consent of the randomized part of the protocol.
- STEP 3 : Patients who have been included in the PADA-1 study, who were randomized for the no-change arm (Arm A) upon rising ESR1 ctDNA;
- STEP 3 : Patients who have recent documented tumor progression (RECIST 1.1).
Exclusion Criteria
- STEP 1 : Locally advanced breast cancer or loco-regional relapse amenable for any treatment with curative intent;
- STEP 1 : 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;
- STEP 1 : Prior endocrine therapy in the metastatic setting is not allowed;
- STEP 1 : 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;
- STEP 1 : Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy;
- STEP 1 : 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 under general anaesthesia);
- STEP 1 : Known active, bleeding diathesis;
- STEP 1 : Any serious known concomitant systemic disorder 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);
- STEP 1 : Patients unable to swallow tablets;
- STEP 1 : History of mal-absorption syndrome or other condition that would interfere with enteral absorption;
- STEP 1 : Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day methylprednisolone equivalent (excluding inhaled steroids);
- STEP 1 : Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment start;
- STEP 1 : Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, palbociclib or any of their excipients;
- STEP 1 : Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia);
- STEP 1 : Patients treated within the last 7 days prior to treatment start in the trial with drug that are known to be CYP3A4 inhibitors, drugs that are known to be CIP3A4 inducers, or with patients who underwent a grapefruit and grapefruit juice cure;
- STEP 1 : Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months;
- STEP 1 : History of previous: Any stage II, III, IV cancer within 5 years preceding patient enrollment in the trial – however multiple breast cancers (controlateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+; Any history of hematological malignancy.
- STEP 1 : Persons deprived of their freedom or under guardianship or incapable of giving consent;
- STEP 1 : Pregnancy or lactation period. Women of childbearing potential must implement adequate nonhormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.
- STEP 2 : Patients who have stopped the aromatase inhibitor therapy for more than 4 consecutive weeks;
- STEP 2 : Patients with a visceral crisis linked to their underlying breast cancer;
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 22 Mar 2017 | 1000 |
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 |
|---|---|---|---|---|---|---|
LETROZOLE | Test | — | ORAL | 2.5 | 28 | SUB08444MIG |
EXEMESTANE | Test | — | ORAL | 25 | 28 | SUB07492MIG |
ANASTROZOLE | Test | — | ORAL | 1 | 28 | SUB05502MIG |
PALBOCICLIB | Test | — | ORAL | 125 | 28 | SUB177204 |
FULVESTRANT | Test | — | SOLUTION FOR INFUSION | 500 | 28 | SUB13933MIG |