|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|"Estrogen receptor-positive (ER+), HER2 negative (HER2-) Advanced Breast Cancer
|E.1.1.1||Medical condition in easily understood language ||
|E.1.1.2||Therapeutic area ||Diseases [C] - Cancer [C04]
|E.1.3||Condition being studied is a rare disease || No
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|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.
|E.2.2||Secondary objectives of the trial ||
| To compare measures of tumor control duration and overall survival between the
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 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.
|E.2.3||Trial contains a sub-study || Yes
|E.2.3.1||Full title, date and version of each sub-study and their related objectives||
|• Optional Tumor Tissue Biopsy for Molecular Profiling, Section 7.5.1 of protocol
• Additional Pharmacogenomic Research, Section 7.6.2 of protocol
• ECG/PK sub-study, Sections 7.2.2 and 7.3 of protocol
|E.3||Principal inclusion criteria ||
|Patient eligibility should be reviewed and documented by an appropriately qualified 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
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
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 with no alternative pathological or
5. Measurable disease as defined per RECIST v.1.1 or bone-only disease.
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. Willingness and ability to provide tumor tissues (ie, archived formalin fixed paraffin
embedded tissues [block or 12 unstained slides]), which will be used 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. If tumor tissue is not available, then a fresh biopsy will be
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.
|E.4||Principal 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 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
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
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
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
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
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: 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. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any
upper gastrointestinal surgery including gastric resection.
13. Known hypersensitivity to letrozole, or any of its excipients, or to any
14. Known human immunodeficiency virus infection.
15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
that may increase the risk associated with study participation or investigational product
administration or may interfere with the interpretation of study results and, in the
judgment of the investigator, would make the patient inappropriate for entry into this
16. Patients who are investigational site staff members or relatives of those site staff
members or patients who are Pfizer employees directly involved in the conduct of the
17. Participation in other studies within 4 weeks before randomization.
18. Recent or active suicidal ideation or behavior.
|E.5 End points
|E.5.1||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
|E.5.1.1||Timepoint(s) of evaluation of this end point||
|Disease assessment every 12 weeks
Baseline up to 2.5 years.
|E.5.2||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.
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|Disease assessment every 12 weeks
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.188.8.131.52||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| Yes
|E.7.3||Therapeutic confirmatory (Phase III)|| Yes
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || Yes
|E.8.1.5||Parallel group|| Yes
|E.8.1.6||Cross over || No
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| Yes
|E.8.2.2||Placebo || Yes
|E.8.2.4||Number of treatment arms in the trial||2
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || Yes
|E.8.4.1||Number of sites anticipated in Member State concerned||12
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||117
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes
|E.8.6.2||Trial being conducted completely outside of the EEA|| No
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned||
|Korea, Republic of
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|End of Trial in all participating countries is defined as Last Patient Last Visit.
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||2
|E.8.9.1||In the Member State concerned months||1
|E.8.9.1||In the Member State concerned days||
|E.8.9.2||In all countries concerned by the trial years||2
|E.8.9.2||In all countries concerned by the trial months||1