Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer, Metastatic, HER2 negative, Palbociclib
Brief summary
This international, multicenter, prospective single arm Phase II biomarker discovery clinical trial with the primary objective of assessing the association of PFS with gene mutations, gene copy number aberrations and gene signatures in post-menopausal women with hormone receptor positive, HER2-negative metastatic or locally relapsed breast cancer whose disease has progressed after prior adjuvant endocrine therapy or one line systemic treatment, i.e., endocrine treatment or chemotherapy, administered for metastatic disease.
Detailed description
Patients will be treated with the combination of palbociclib and fulvestrant. The primary objective is to assess the association of the primary endpoint progression-free survival (PFS) with potential markers. The trial is included in the AURORA program conducted by the Breast International Group (BIG), an international study aiming to collect and characterize biological samples, including metastatic tissue, from patients with advanced breast cancer. The primary aim of the PYTHIA study is to discover potentially innovative biomarkers for the selection of patients to Palbociclib/Fulvestrant treatment. The strength of the trial lies in its conduct in conjunction with the AURORA study, which systematically evaluates a panel of biomarkers in tissue and blood, in a certified central lab. Stemming from this association, an abundance of molecular profiling information will become available for different biological samples. Additional molecular and functional imaging assessments performed within the context of the PYTHIA study increase its scientific merit, since it will represent a prospective, systematic effort to identify biomarkers for patient stratification, integrating several molecular profiling assessments.
Interventions
DRUGPalbociclib
125 mg, orally, daily for 3 weeks followed by 1 week off; repeated at every 28 days cycle until progression, lack of tolerability, or patient declines further protocol treatment.
DRUGFulvestrant
500mg, intramuscularly on days 1 and 15 of cycle 1, then on day 1 (+/- 3 days) of every 28 days cycle until progression, lack of tolerability, or patient declines further protocol treatment.
Sponsors
ETOP IBCSG Partners Foundation
Breast International Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female gender * Age ≥ 18 years * Postmenopausal, defined as women with: * Prior bilateral surgical oophorectomy; or * Amenorrhea and age ≥ 60 years; or * Age \< 60 years and amenorrhea for 12 or more consecutive months in the absence of alternative pathological or physiological cause and FSH and serum estradiol levels within the laboratory's reference ranges for postmenopausal women. * Endocrine resistant disease, defined as one of: * Relapse while on adjuvant endocrine therapy; * Relapse within 12 months after completion of adjuvant endocrine therapy; * Progression of disease under first line endocrine therapy for metastatic and/or loco-regionally advanced breast cancer. Note: Patient may have received one prior chemotherapy for advanced or metastatic breast cancer. * ER positive tumor and HER2-negative tumor, as assessed locally * ECOG Performance Status 0-1. * Measurable or non-measurable but evaluable disease according to RECIST 1.1. * Written Informed Consent (IC) for screening procedures. * Written informed consent to participate in the AURORA program of BIG. * The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines. * Life expectancy \>3 months. * Hematological status: * Absolute neutrophil count ≥ 1.5 × 109/L * Platelet count ≥ 100 × 109/L * Hemoglobin ≥ 9 g/dL * Hepatic status: * Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). * AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤ 5 × ULN. * Glucose in normal range, or well-controlled diabetes defined as an HbA1c level ≤ 7.5%. * Renal status: \- Creatinine ≤ 1.5 ×ULN or creatinine clearance \> 60 ml/min. * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant. * Ability to swallow oral medication.
Exclusion criteria
* Prior use of fulvestrant or any CDK inhibitor. * More than one prior line of chemotherapy for metastatic or locally relapsed disease. * Previous or current non-breast malignancies 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. * Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. * Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (NYHA functional classification ≥3), cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism. * QTc exceeding 480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP). * Uncontrolled electrolyte disorders that can reinforce the QT-prolonging effect of the drug (e.g., hypocalcemia, hypokalemia, hypomag¬nesemia). * Known history of HIV seropositivity. HIV screening is not required at baseline. * Uncontrolled diabetes defined as HbA1c level \> 7.5%. * Concurrent disease or familial, sociological or geographical condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient's safety. * Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent. * Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant. * Treatment with an investigational agent in the 4 weeks before enrollment. * Concurrent treatment with any of the drugs not permitted * Adverse events (except alopecia) from previous systemic cancer therapy, radiotherapy or surgery have not recovered to CTCAE v4.0 grade 1 or resolved prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With and Without Progression Free Survival (PFS) Events | Maximum 36 months | Time from treatment initiation until documented disease progression according to RECIST 1.1 or death, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | From date of enrolment until patient's end of treatment visit (or a maximum of 12 months after EoT in the absence of tumor progression), assessed up to 48 months. | Best overall response is based on RECIST (Response evaluation criteria in solid tumors) 1.1 criteria and is defined as best response recorded from enrollment across all time points until disease progression. Confirmation of partial response (PR) or complete response (CR) by an additional scan was not requested in this trial (rationale: initially because of randomized placebo-controlled design; subsequently because no hypothesis testing of progression-free survival, PFS, distribution relative to an historical control). |
| Best Overall Response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) | From date of enrolment until patient's end of treatment visit (or a maximum of 12 months after EoT in the absence of tumor progression), assessed up to 48 months. | Disease control is defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) (or non-CR/non-PD, progressive disease, in the case of non-measurable disease only) lasting for at least 24 weeks, measured from enrollment until first documentation of progressive disease |
Countries
Belgium, Italy, United Kingdom
Contacts
STUDY_CHAIRLuca Malorni, MD PhD
USL4 Hospital of Prato, Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Palbociclib plus Fulvestrant
Palbociclib: 125 mg, orally, daily for 3 weeks followed by 1 week off; repeated at every 28 days cycle until progression, lack of tolerability, or patient declines further protocol treatment.
Fulvestrant: 500mg, intramuscularly on days 1 and 15 of cycle 1, then on day 1 (+/- 3 days) of every 28 days cycle until progression, lack of tolerability, or patient declines further protocol treatment. | 122 |
| Total | 122 |
Baseline characteristics
| Characteristic | Experimental |
|---|---|
| Age, Customized 40-49 years | 15 Participants |
| Age, Customized <40 years | 2 Participants |
| Age, Customized 50-59 years | 37 Participants |
| Age, Customized 60-69 years | 42 Participants |
| Age, Customized 70-79 years | 23 Participants |
| Age, Customized 80+ years | 3 Participants |
| Region of Enrollment Belgium | 73 participants |
| Region of Enrollment Italy | 46 participants |
| Region of Enrollment United Kingdom | 3 participants |
| Sex: Female, Male Female | 122 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 30 / 122 |
| other Total, other adverse events | 0 / 122 |
| serious Total, serious adverse events | 89 / 122 |
Outcome results
Primary
Number of Participants With and Without Progression Free Survival (PFS) Events
Time from treatment initiation until documented disease progression according to RECIST 1.1 or death, whichever occurs first
Time frame: Maximum 36 months
Population: Patients who initiate treatment and have the target disease.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental | Number of Participants With and Without Progression Free Survival (PFS) Events | PFS event, Yes | 92 Participants |
| Experimental | Number of Participants With and Without Progression Free Survival (PFS) Events | PFS event, No | 30 Participants |
Secondary
Best Overall Response
Best overall response is based on RECIST (Response evaluation criteria in solid tumors) 1.1 criteria and is defined as best response recorded from enrollment across all time points until disease progression. Confirmation of partial response (PR) or complete response (CR) by an additional scan was not requested in this trial (rationale: initially because of randomized placebo-controlled design; subsequently because no hypothesis testing of progression-free survival, PFS, distribution relative to an historical control).
Time frame: From date of enrolment until patient's end of treatment visit (or a maximum of 12 months after EoT in the absence of tumor progression), assessed up to 48 months.
Population: Patients who initiate treatment and have the target disease.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental | Best Overall Response | Complete response (CR) | 6 Participants |
| Experimental | Best Overall Response | Partial response (PR) | 20 Participants |
| Experimental | Best Overall Response | Stable disease (SD) | 80 Participants |
| Experimental | Best Overall Response | Progressive disease (PD) | 16 Participants |
Secondary
Best Overall Response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD)
Disease control is defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) (or non-CR/non-PD, progressive disease, in the case of non-measurable disease only) lasting for at least 24 weeks, measured from enrollment until first documentation of progressive disease
Time frame: From date of enrolment until patient's end of treatment visit (or a maximum of 12 months after EoT in the absence of tumor progression), assessed up to 48 months.
Population: Patients who initiate treatment and have the target disease.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental | Best Overall Response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) | Disease control not observed | 33 Participants |
| Experimental | Best Overall Response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) | Disease control observed (CR or PR or SD) | 89 Participants |