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 mutant.
Inclusion Criteria (Preliminary Screening)
1. Signed Preliminary Screening Informed Consent Form obtained prior to any study
specific assessments and procedures
2. Age ≥18 years (or per national guidelines)
3. Patients 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. Patients must agree to provide a representative formalin-fixed paraffin-embedded
(FFPE) tumor tissue block (preferred) from primary breast or metastatic site
(archival) OR at least 15 freshly cut unstained slides from such a block, along with a
pathology report documenting HER2 positivity and hormone receptor positivity.
6. Patients should be willing to provide a representative tumor specimen obtained from
recently biopsied metastatic disease if clinically feasible. This is recommended but
Inclusion Criteria (Randomization Screening)
7. Signed Main Informed Consent Form 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
which is 6 months after the last treatment with palbociclib if they are in Arm A and
for 7 months after last treatment with trastuzumab if in either Arm A or Arm B
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) 12 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
Prior Treatment Specifics
14. 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
15. 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 can randomize immediately
following completion of their induction therapy, or for those who have already
completed induction, a gap of 12 weeks between their last infusion/dose of induction
therapy and the C1D1 visit is permitted. Patients are eligible provided they are
without evidence of disease progression by local assessment (i.e. CR, PR or SD).
16. Patients with a history or presence of asymptomatic 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 induction 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
Baseline Body Function Specifics
17. Absolute neutrophil count ≥ 1,000/mm3
18. Platelets ≥ 100,000/mm3
19. Hemoglobin ≥ 10g/dL
20. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin
within normal range in patients with documented Gilbert's Syndrome.
21. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤
3 × institutional ULN (≤5 x ULN if liver metastases are present).
22. Serum creatinine below the upper limit of normal (ULN) of the institutional normal
range or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine
levels above institutional ULN.
23. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either
ECHO or MUGA
Exclusion Criteria (Randomization)
1. Concurrent therapy with other Investigational Products.
2. Prior therapy with any CDK 4/6 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 (see Section 8.6.3 for
list of strong inhibitors or inducers of CYP3A isoenzymes).
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 >480 msec, 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