Postmenopausal pretreated HER2-positive locally advanced or metastatic breast cáncer patients
Conditions
Interventions
Product Name: Palbociclib (PD-0332991)
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: -
CAS Number: -
Current Sponsor code: PD-
Sponsors
SOLTI
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures. 2. Female patients. 3. Age >= 18 years. 4. ECOG Performance Status of 0 or 1. 5. Locally-confirmed HER2-positive invasive breast cancer, defined by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice guideline (Wolff JCO 2013) as: a. 3+ overexpression by IHC (circumferential, intense membrane staining that is complete, intense observed within of >10% of invasive tumor cells). b. Positive in situ hybridization (ISH: FISH/CISH/SISH within >10% of invasive tumor cells and by counting at least 20 cells within the area) based on: - Single-probe average HER2 gene copy number >=6.0 signals/cell - Dual-probe HER2/CEP17 ratio >=2.0 with an average HER2 gene copy number >=4.0 signals/cell - Dual-probe HER2/CEP17 ratio >=2.0 with an average HER2 gene copy number =6.0 signals/cell 6. Known hormone receptor status, as assessed locally and defined according to ASCO/CAP guidelines as positive for ER o PR if finding of >=1% of tumor cell nuclei are immunoreactive. 7. Histologically confirmed adenocarcinoma of the breast with locally advanced or MBC. a. Patients with locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent. Patients with available standard curative options are not eligible. b. For patients with bilateral breast cancer, HER2-positivity must be demonstrated in both locations or in a metastatic biopsy. 8. At least two, but no more than four prior lines of prior systemic anti-cancer therapy for recurrent locally advanced or MBC, which must include trastuzumab or other anti-HER2 therapy in combination with a taxane or capecitabine. Prior treatment may include hormonal agents, other anti-HER2 targeted agents (e.g., lapatinib, neratinib, pertuzumab, TDM1), or other chemotherapies. 9. Availability of tumor tissue for biomarker analysis, either from metastatic lesions (preferred) or from primary tumor. 10. Measurable or non-measurable (but evaluable) disease, as per RECIST 1.1 criteria. 11. Adequate organ function, as determined by the following laboratory tests, within 14 days prior to randomization: a. Absolute neutrophil count (ANC) >=1.5 x 109/L b. Hemoglobin (Hb) >=9 g/dL (red blood cell transfusion and/or erythropoietin allowed) c. Platelets >100,000/mm3 d. Serum creatinine =50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan. 13. Postmenopausal status defined either by: prior bilateral oophorectomy, age >60 or age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen or ovarian suppression) and FSH and estradiol in the postmenopausal range per local range. 14. Absence of any psychological, familial, sociological or geo
Exclusion criteria
Exclusion criteria: 1. Treatment with any anticancer investigational drug within 14 days prior to commencing study treatment. 2. Having received more than four lines of prior treatment (anti-HER2 agent in combination with chemotherapy) for advanced disease. 3. Prior treatment with a cell cycle inhibitor compound. 4. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome. 5. Brain metastases that have not been treated previously, are progressive, or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms within 30 days prior to the first study treatment dose. 6. Radiotherapy for metastatic sites of disease outside of the brain performed within 14 days prior to study enrollment and/or radiation of > 30% of marrow-bearing bone. 7. Symptomatic hypercalcemia requiring use of bisphosphonate therapy within 21 days prior to the first study treatment. Patients who receive bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. 8. Abnormal liver function as defined by the following: a. AST or ALT > 2.5 x ULN b. AST or ALT > 5 x ULN if liver metastases c. AST or ALT > 1.5 x ULN with concurrent serum alkaline phosphatase > 2.5 x ULN. Serum alkaline phosphatase may be > 2.5 x ULN only if bone metastases are present and AST (SGOT) and ALT (SGPT) 400 mg/m2 b. Epirubicin> 720 mg/m2 c. Mitoxantrone> 120 mg/m2 d. Idarubicin> 90 mg/m2 e. If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 400 mg/m2 doxorubicin. 10. Cardiopulmonary dysfunction as defined by: a. Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic > 100 mm Hg) despite optimal medical management. b. Inadequately controlled angina or serious cardiac arrhythmia not controlled by adequate medication. c. Inadequate LVEF at baseline, as defined as LVEF <50% by either ECHO or MUGA scan. d. History of symptomatic congestive heart failure (CHF): Grade ? 3 per NCI CTCAE version 4.0 or Class ? II New York Health Association (NYHA criteria). e. History of a decrease in LVEF to <40% or symptomatic CHF with prior trastuzumab treatment. f. Myocardial infarction within 6 months prior to randomization. g. Current dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy. 11. Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures). 12. Patients who are biologically capable of having children 13. M
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Measured as the proportion of patients free of progression after 6 months on study treatment (PFS6).;Timepoint(s) of evaluation of this end point: 6 Months;Main Objective: To test the efficacy of the combination of palbociclib plus trastuzumab with or without letrozole in HER2-positive metastatic breast cancer patients who have been previously treated with trastuzumab in combination with chemotherapy, measured as the proportion of patients free of progression after 6 months on study treatment (PFS6).; Secondary Objective: - To assess the disease control rate (DCR), measured as the proportion of patients who achieve an objective response, or disease stabilization during at least 12 weeks on treatment using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. - To assess the tumor overall objective response rate (ORR) using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. - To describe the safety profile of the combinations - To assess the time to progression (TTP) to study treatment - To test cardiac safety of study treatment - To assess overall survival - To investigate biomarkers of response to the study treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Patients with objective response (complete or partial) or stable disease according to RECIST 1.1 criteria with a duration of at least 12 weeks. -Patients achieving complete response and/or partial response, according to the RECIST 1.1 criteria throughout the study treatment. -To assess the safety profile of the combinations according to any grade adverse events, grade III and IV of adverse events, any dose reduction caused by adverse events and withdrawal caused by adverse events. To the adverse event grade will be evaluated according to CTCAE v 4.03. - Time to progression defined as the period of time from treatment allocation to disease progression. - Frequency of any grade cardiac events , frequency of grade III-IV cardiac events according to NYHA classification. - Overall Survival, measured as the time from allocation to death from any cause. -Studying genes and molecular signatures . ;Timepoint(s) of evaluation of this end point: At the end of study | — |
Countries
Spain
Contacts
Public ContactOFICINA OPERACIONES
SOLTI
Outcome results
None listed