The primary objective of this study is to demonstrate that the combination of palbociclib
with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus
endocrine therapy alone in improving the outcomes of subjects with hormone
receptor-positive, HER2+ metastatic breast cancer.
Subjects will be randomized into one of two treatment arms following minimum of 4 and
maximum of 8 cycles of induction treatment with anti-HER2 therapy. Arm A subjects will
receive the experimental therapy, palbociclib, in addition to their current anti-HER2
therapy and endocrine therapy. Arm B subjects will continue to receive the anti-HER2
therapy. It is expected that the addition of palbociclib to the first-line treatment of HER2
disease will delay the onset of therapeutic resistance and ultimately prolong the survival
of patients with metastatic breast cancer. The study is designed to treat the subset of
patients with HER2+ disease who are also hormone receptor positive (HR+). It is also
expected that palbociclib will modulate the endocrine resistance in HER2+/HR+ disease and
potentiate the benefits of anti-HER2 therapy. Lastly, the current study includes a
comprehensive molecular characterization of the disease at study entrance which will allow
us to investigate the benefits of palbociclib in subsets of HER2+/HR+ disease such as PIK3CA
Inclusion Criteria (Screening)
1. Signed informed consent obtained prior to any study specific assessments and
2. Age ≥18 years (or per national guidelines)
3. Participants must have histologically confirmed invasive breast cancer that is
metastatic or not amenable for resection or radiation therapy with curative intent.
Histological documentation of metastatic/recurrent breast cancer is not required if
there is unequivocal evidence for recurrence of the breast cancer.
4. Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+
and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be
performed according 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 (American Society of Clinical
Oncology/College of American Pathologists) guidelines.
5. Representative formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred)
or at least 15 unstained slides along with a pathology report documenting HER2
positivity and hormone receptor positivity
6. Representative tumor specimen obtained from metastatic disease if clinically
feasible. This could include tumor obtained from metastatic biopsies performed for
diagnostic purpose or biopsies performed as part of the current study.
Inclusion Criteria (Randomization)
7. Signed informed consent obtained prior to any study specific assessments and
8. Age ≥ 18 years (or per national guidelines)
9. ECOG performance status 0-1
10. Patients must be able and willing to swallow and retain oral medication without a
condition that would interfere with enteric absorption.
11. 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 the study 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. Adequate contraception is defined as one highly effective form (i.e.
abstinence, (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and
condom / occlusive cap with spermicidal foam / gel / film / cream / suppository).
12. Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy
regimen 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) 3-6 weeks
between last dose of chemotherapy-anti-HER2therapy and randomization are allowed.
Endocrine therapy could start before study randomization.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other study procedures
14. 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 Prior Treatment Specifics
15. Patients may or may not have received neo/adjuvant therapy, but must have a
disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6
16. Patients must have received an acceptable, standard, chemotherapy containing
anti-HER2 based induction therapy for the treatment of metastatic breast cancer prior
to study enrollment. For this study, chemotherapy is limited to a taxane or
vinorelbine (only for trastuzumab-based regimen). Eligible patients are expected to
have completed 6 cycles of chemotherapy containing anti-HER2-therapy treatment. A
minimum of 4 cycles of treatment is acceptable for patients experiencing significant
toxicity associated with treatment as long as they are without evidence of disease
progression (i.e. CR, PR or SD). The maximum number of cycles is 8. Patients are
eligible provided they are without evidence of disease progression by local
assessment (i.e. CR, PR or SD).
17. Participants with a history of treated CNS metastases are eligible, provided they
meet all of the following criteria:
- Disease outside the CNS is present.
- No evidence of interim progression between the completion of CNS directed
therapy and the screening radiographic study
- No history of intracranial hemorrhage or spinal cord hemorrhage
- Not requiring anti-convulsants for symptomatic control
- Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and
recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement
for corticosteroid Baseline Body Function Specifics
18. Absolute neutrophil count ≥ 1,000/mm3
19. Platelets ≥ 100,000/mm3
20. Hemoglobin ≥ 10g/dL
21. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin
within normal range in patients with documented Gilbert's Syndrome.
22. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤
1.5 × institutional ULN.
23. Serum creatinine within normal institutional limits or creatinine clearance ≥ 60
mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.
24. Left ventricular ejection fraction (LVEF)≥ 50% at baseline (within 42 days of
randomization) as determined by either ECHO or MUGA
Exclusion Criteria (Randomization)
1. Concurrent therapy with other Investigational Products.
2. Prior therapy with any CDK inhibitor.
3. History of allergic reactions attributed to compounds of chemical or biologic
composition similar to palbociclib.
4. Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A isoenzymes within 7 days of randomization.
5. Uncontrolled current 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.
6. 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
7. 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.
8. QTc interval >480msec, Brugada syndrome or known history of QTc prolongation or
Torsade de Pointes.
9. Patients with clinically significant history of liver disease, including viral or
other known hepatitis, current alcohol abuse, or cirrhosis