Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy after Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer

Protocol # :
HER-2 Positive Breast Cancer
Estrogen Receptor Positive Breast Cancer
Disease Sites
Principal Investigator
Metzger, Otto
Site Investigator
Briccetti, Frederick
Faggen, Meredith, G.
Site Research Nurses
Campbell, Margaret
Caradonna, Lisa
Caradonna, Lisa
Casella, Allison
Germon, Victoria
Hassett, Michael
Hixon, Nicole, R.
Huff, Kimberly
Kasparian, Elizabeth
Kosinski, Michelle
LaPointe, Janet
Lehnus, Jaclyn
Macauley, Colleen
Marchetti, Kelly
Morse, Linda, K.
O'Neil, Kelly
Pasquale, Kathryn, Mary
Piper, Audrey, L.
Roche, Kathleen, A.
Rutter, Morgan
Weeks, Kristie
Wong, Christine

Trial Description

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.

Eligibility Requirements

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
optional tissue.

Inclusion Criteria (Randomization Screening)

7. Signed Main Informed Consent Form obtained prior to any study specific assessments
and procedures

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 /

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 months.

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 for corticosteroid

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

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