PALbociclib CoLlaborative Adjuvant Study:
A randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for hormone receptor positive (HR+) / human epidermal growth factor receptor 2 (HER2)-negative early breast cancer

(1) Signed informed consent obtained prior to any study specific assessments
and procedures.
(2) Age >=18 years (or per national guidelines).
(3) Premenopausal and postmenopausal women or men with Stage II (Stage IIA
limited to a max. of 1000 patients) or Stage III early invasive breast cancer
per AJCC Breast Cancer Staging version 7 /UICC . Baseline staging to document
absence of metastatic disease is not required, however is recommended as
determined by institutional practice.
(4) Patients with multicentric and/or multifocal and/or bilateral early
invasive breast cancer whose histopathologically examined tumors all meet
pathologic criteria for ER+ and/or PR+ and HER2-.
(5) Patients must have histologically confirmed hormone receptor positive (ER+
and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 measurements
should be performed acc. to institutional guidelines, in a CLIA-approved
setting in the US or certified laboratories for Non-US regions. Cut-off values
for positive/negative staining should be in accordance with current ASCO/CAP
guidelines. Patients with equivocal HER2 in situ hybridization results
according to current ASCO/CAP guidelines are eligible, as long as they have not
received and are not scheduled to receive anti-HER2 treatment. Testing may
occur on diagnostic core or surgical tumor tissue.
(6) Patients must have undergone adequate (definitive) breast surgery for the
current malignancy.
(7) A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be
transmitted to a central sample repository and confirmation of receipt must be
available prior to randomization.
(8) ECOG performance status 0-1.
(9) Patients must be able and willing to swallow and retain oral medication
without a condition that would interfere with enteric absorption.
(10) Serum or urine pregnancy test must be negative within 7 days of
randomization in women of childbearing potential. Pregnancy testing does not
need to be pursued in patients who are judged as postmenopausal before
randomization, as determined by local practice, or who have undergone bilateral
oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of
childbearing potential and male patients randomized into treatment Arm A or B
must use adequate contraception for the duration of protocol treatment and for
6 months after the last treatment with palbociclib if they are in arm A. In
addition, patients receiving standard adjuvant endocrine therapy (Arm A and Arm
B) should use adequate contraception in accordance with the specific medication
requirements (e.g. SmPC).Prior Treatment Specifics
(11) Patients may or may not have received neo/adjuvant therapy, but must be
after last dose of chemotherapy and/or biologic therapy and must have
sufficient resolution of side effects per physician assessment at the time of
randomization.
(12) Patients may or may not have received breast/axilla/post-mastectomy chest
wall radiotherapy, but must be after last dose of radiotherapy and must have
sufficient resolution of side effects per physician assessment at the time of
randomization.
(13) Patients must have sufficient resolution of any surgical side effects from
the last surgery per physician assessment with no active wound healing
complications at the time of randomization.
(14) Patients must either be initiating or have already started adjuvant
hormonal treatment. Patients may already have initiated endocrine therapy at
the time of randomization, but randomization must take place within 12 months
of date of histological diagnosis and within 6 months of initiating standard
adjuvant endocrine therapy. Patients who received neoadjuvant endocrine therapy
are eligible as long as they are randomized within 12 months of initial
histological diagnosis and after completing no more than 6 months of adjuvant
endocrine therapy. Patients may be receiving either tamoxifen or aromatase
inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal
patients and men, concurrent LHRH agonist use is allowable and may also be
ongoing at the time of randomization. If a LHRH agonist was used for ovarian
protection during neo / adjuvant chemotherapy it is allowable and shall not be
taken into account for calculations regarding the 6 months standard adjuvant
endocrine therapy.Baseline Body Function Specifics
(15) Absolute neutrophil count >= 1,500/mm3
(16) Platelets >= 100,000/ mm3
(17) Hemoglobin >= 10g/dL
(18) Total serum bilirubin <= ULN; or total bilirubin <= 3.0 × ULN with direct
bilirubin within normal range in patients with documented Gilbert*s Syndrome.
(19) Aspartate amino transferase (AST or SGOT) and alanine amino transferase
(ALT or SGPT) <= 1.5 × institutional ULN.
(20) Serum creatinine below the upper limit of the institutional normal range
(ULN) or creatinine clearance (or glomerular filtration rate (GFR) >= 60
mL/min/1.73 m2 for patients with serum creatinine levels above institutional
ULN.






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(1) Concurrent therapy with other Investigational Products.
(2) Prior therapy with any CDK inhibitor.
(3) Patients with Stage I or IV breast cancer are not eligible. Baseline
staging to document absence of metastatic disease is not required, however is
recommended as determined by institutional practice.
(4) History of allergic reactions attributed to compounds of chemical or
biologic composition similar to palbociclib.
(5) Patients receiving any medications or substances that are potent inhibitors
or inducers of CYP3A isoenzymes within 7 days of randomization.
(6) Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social
situations that would limit compliance with study requirements. Ability to
comply with study requirements is to be assessed by each investigator at the
time of screening for study participation.
(7) Pregnant women, or women of childbearing potential without a negative
pregnancy test (serum or urine) within 7 days prior to randomization,
irrespective of the method of contraception used, are excluded from this study
because the effect of palbociclib on a developing fetus is unknown.
Breastfeeding must be discontinued prior to study entry.
(8) Patients with a history of any malignancy are ineligible except for the
following circumstances:
• Patients with a malignancy history other than invasive breast cancer are
eligible if they have been disease-free for at least 5 years and are deemed by
the investigator to be at low risk for recurrence of that malignancy.
• Patients with the following cancers are eligible, even if diagnosed and
treated within the past 5 years: ductal carcinoma in situ of the breast,
cervical cancer in situ, and non-metastatic non-melanomatous skin cancer.
(9) Patients are not eligible if they have previously received endocrine
therapy within 5 years prior to diagnosis of the current malignancy. This
includes use for prophylactic reasons, including treatment of osteoporosis or
cancer prevention with tamoxifen, raloxifene or AI. Patients may concurrently
receive bisphosphonates or rank ligand inhibitors while on this study if
necessary for treatment or prevention of osteopenia or osteoporosis.
(10) Patients on combination antiretroviral therapy, i.e. those who are
HIV-positive, are ineligible because of the potential for pharmacokinetic
interactions or increased immunosuppression with palbociclib.
(11) Patients with clinically significant history of chronic liver disease,
including chronic / active viral or other known hepatitis, current alcohol
abuse, or cirrhosis, etc.
(12) Patients receiving concurrent exogenous hormone therapy (hormone
replacement therapy, oral or any other hormonal contraceptives such as hormonal
contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy
is allowable.