Patients with hormonal receptor positive and HER2 negative MBC who are resistant to prior NSAI therapy. MedDRA version: 16.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: Palbociclib
Product Code: PD-0332991
Pharmaceutical Form: Capsule
INN or Proposed INN: NA
CAS Number: 571190-30-2
Current Sponsor code: PD-0332991
Concentration unit: mg milligram(s)
Con
Sponsors
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.The patient has signed the informed consent document. 2.Females with histologically confirmed MBC whose disease is resistant to previous non-steroidal aromatase inhibitors (letrozole or anastrozole), defined as: ? Recurrence while on or within 12 months after the end of adjuvant treatment with NSAI or ? Progression while on or within 1 month after the end of treatment with NSAI for advanced disease. 3.Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or first line therapy for MBC. 4.It is not mandatory to have letrozole or anastrozole as the most recent treatment before randomization but progression of the MBC documented during receipt of the most recent systemic therapy before randomization should be documented. 5.Hormonal receptor positive (HR+) breast cancer based on local laboratory determination. HR+ defined as ? 1% positive cells by IHC for ER and/or PgR. 6.Documented HER2 negative breast cancer based on local laboratory determination on most recent tumor biopsy. HER2 negative tumor is determined as IHC score 0 or 1+ or negative by ISH (FISH/CISH/SISH) defined as a HER2/CEP17 ratio =65 years) yes F.1.3.1 Number of subjects for this age range 348
Exclusion criteria
Exclusion criteria: 1. Have received more than 1 prior chemotherapy regimen for MBC. NOTE: Other previous anticancer endocrine treatments for advanced disease are allowed. 2. Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis and over 50% liver involvement). 3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, 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 (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization. 4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor [any agent whose mechanism of action is to inhibit the PI3 kinase-mTOR pathway] or capecitabine. 5. Prior treatment with exemestane in the metastatic setting. If the patient has received exemestane in the adjuvant setting and developed MBC, she will be eligible for the study provided: ? She has received letrozole/anastrozole as first-line MBC and progressed. ? At least 1 year has elapsed since the end of adjuvant exemestane treatment. 6. Patients treated within the last 7 days prior to randomization with: ? Food or drugs that are known to be CYP3A4 inhibitors ? Drugs that are known to be CYP3A4 inducers ? Drugs that are known to prolong the QT interval 7. Major surgery, chemotherapy, radiotherapy, any investigational agent or other anti-cancer therapy within 4 weeks before randomization. Patients who received prior radiotherapy to ? 25% of bone marrow are not eligible independent of when it was received. 8. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 9. QTc > 480msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP). 10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcemia, hypokalemia, hypomagnesemia). 11. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ? 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism. 12. Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease or chronic diarrhea. 13. Known hypersensitivity to exemestane, palbociclib, capecitabine or any of their excipients. 14. Any of the following contraindications for chemotherapy with capecitabine: ? Known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase. ? Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related analogues, such as brivudine. 15. Known human immunodeficiency virus infection. 16. Other severe acute or chronic medical or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate that palbociclib in combination with exemestane is superior to capecitabine in prolonging Progression-Free Survival (PFS) in postmenopausal women with HR positive/HER2 negative MBC whose disease was resistant to non-steroidal aromatase inhibitors.;Primary end point(s): - Progression-Free Survival (PFS).;Timepoint(s) of evaluation of this end point: Approximately 36 months from the start of study randomization.;Secondary Objective: - To compare other efficacy measures between the treatment arms. - To compare safety and tolerability between the treatment arms. - To evaluate the Pharmacokinetics (PK) of the combination of exemestane with palbociclib (in selected sites and only in patients accepting to participate). - To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle (e.g, CCND1 amplification, CDKN2A deletion), drug targets (e.g. CDK 4/6), tumor sensitivity and/or resistance (e.g. Ki67, pRb, PIK3CA mutation, CCNE1 expression). - To compare health related quality of life between the treatment arms. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Objective Response Rate (ORR): Complete Response (CR) plus Partial Response (PR) divided by the number of patients randomized with measurable disease. - Clinical Benefit Rate (CBR): CR plus PR plus stable disease lasting more than 24 weeks divided by all randomized patients (ITT population). - Response Duration (RD). - Overall Survival (OS). - 1 year and 2 year survival probabilities. - Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0.;Timepoint(s) of evaluation of this end point: - Efficacy endpoints will be assessed at the end of the study. - Safety will be assessed along the cycles. | — |
Countries
Austria, Hungary, Ireland, Latvia, Spain
Contacts
Public ContactClinical Operations Department
GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
Outcome results
None listed