"Estrogen receptor-positive (ER+), HER2 negative (HER2-) Advanced Breast Cancer (ABC)"
Conditions
Interventions
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)
Concentration type: up to
Con
Sponsors
Pfizer Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patient eligibility should be reviewed and documented by an appropriate member of the investigator’s study team before patients are included in the study. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Adult women (= 18 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated. 2. Documentation of histologically or cytologically confirmed diagnosis of estrogen-receptor positive (ER+) breast cancer based on local laboratory results. 3. Previously untreated with any systemic anti-cancer therapy for their locoregionally recurrent or metastatic ER+ disease. 4. Postmenopausal women defined as women with: ? Prior bilateral surgical oophorectomy, or ? Medically confirmed post-menopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months or follicle-stimulating hormone (FSH) and estradiol blood levels in their respective postmenopausal ranges with no alternative pathological or physiological cause. 5. Measurable disease as defined per RECIST v.1.1 or bone-only disease (with bone lesions confirmed by CT, MRI or bone X-ray). Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. 7. Adequate organ and marrow function defined as follows: ? ANC =1,500/mm3 (1.5 x 109 /L); ? Platelets =100,000/mm3 (100 x 109 /L); ? Hemoglobin =9 g/dL (90 g/L); ? Serum creatinine =1.5 x ULN or estimated creatinine clearance = 60 mL/min as calculated using the method standard for the institution; ? Total serum bilirubin =1.5 x ULN (=3.0 x ULN if Gilbert’s disease); ? AST and/or ALT =3 x ULN (=5.0 x ULN if liver metastases present); ? Alkaline phosphatase =2.5 x ULN (=5.0 x ULN if bone or liver metastases present). 8. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade =1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). 9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 10. All patients must agree to provide tumor tissues for centralized retrospective confirmation of ER status and to evaluate correlation between genes, proteins, and RNAs relevant to the cell cycle pathways and sensitivity/resistance to the investigational agents. Freshly biopsied, recurrent/metastatic tumor samples must be provided whenever possible. If such a biopsy is not feasible or cannot be safely performed, then an archived tumor sample may be accepted. In either case a formalin fixed, paraffin embedded(FFPE) block or 12 unstained FFPE slides are required for patient participation. 11. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 433 F.1.3 Elderly (>=65
Exclusion criteria
Exclusion criteria: Patients presenting with any of the following will not be included in the study: 1. HER2-positive tumor as defined by documentation of erbB-2 gene amplification by FISH (as defined by a HER2/CEP17 ratio =2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer's kit instruction) or INFORM HER2 dual ISH (as defined by manufacturer's kit instruction) or documentation of HER2 overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory results utilizing one of the sponsor-approved assays. If HER2 status is unavailable or was determined using a test other than a sponsor-approved assay, then testing must be performed/repeated using one of these assays prior to randomization. If tissue sample from both primary and recurrent/metastatic tumors are available, HER2 assessment from the most recent sample (i.e., recurrent/metastatic sample) should be used to define eligibility whenever feasible. 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 neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment. 5. Prior treatment with any CDK4/6 inhibitor. 6. Patients treated within the last 7 days prior to randomization with: ? Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice); ? Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s wort). ? Drugs that are known to prolong the QT interval. 7. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 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 >480 msec (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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate that the combination of PD-0332991 with letrozole is superior to placebo plus letrozole in prolonging PFS in postmenopausal women with ER(+)/HER2 (-) advanced breast cancer who have not received any prior systemic anti-cancer therapies for their advanced/metastatic disease.;Secondary Objective: ? To compare measures of tumor control duration and overall survival between the treatment arms; ? To compare safety and tolerability between the treatment arms; ? To compare health related quality of life between the treatment arms; ? To characterize the effects of PD-0332991 at therapeutic doses in combination with letrozole on QTc interval in this patient population; ? To determine trough PD-0332991 plasma concentration in this patient population and explore correlations between exposure and response and/or safety findings; ? To characterize alterations in genes, proteins, and ribonucleic acids (RNAs) relevant to the cell cycle (eg, CCND1 amplification, CDKN2A deletion), drug targets (eg, CDK 4/6), and tumor sensitivity and/or resistance (eg, Ki67, pRb) in tumor tissues.;Primary end point(s): Progression-Free Survival (PFS). Median time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. ;Timepoint(s) of evaluation of this end point: Disease assessment every 12 weeks Baseline up to 2.5 years. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): ? Overall Survival (OS); ? 1-year, 2-year, and 3-year survival probabilities; ? Objective Response (OR: Complete Response or Partial Response); ? Duration of Response (DR); ? Disease Control (DC: CR+PR+Stable disease =24 weeks); ? Corrected QT interval (QTc); ? Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1, CDKN2A), proteins (eg, Ki67, pRb), and RNA expression (eg, cdk4, cdk6); ? Trough plasma concentration of PD-0332991; ? EuroQol (EQ-5D) Score; ? Functional Assessment of Cancer Therapy - Breast (FACT-B); ? Type, incidence, severity (as graded by NCI CTCAE v4.0), seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities.;Timepoint(s) of evaluation of this end point: Disease assessment every 12 weeks | — |
Countries
Australia, Belgium, Brazil, Canada, China, Czechia, European Union, France, Germany, Hungary, Ireland, Italy, Japan, Korea, Republic of, New Zealand, Poland, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactClinical Trials.gov Call Center
Pfizer Inc
Outcome results
None listed