T-DM1 and Palbociclib for Metastatic HER2 Breast Cancer

This is a multi-center, randomized, phase II study of T-DM1 with or without palbociclib in
the treatment of patients with metastatic HER2-positive breast cancer. Patients will be
randomized 1:1 to T-DM1 with or without palbociclib.

Hypotheses: Combination of T-DM1 with palbociclib improves progression free survival compared
to single agent T-DM1

Primary objective: Compare progression free survival of the combination arm (T-DM1 with
palbociclib) to single agent T-DM1

Secondary objectives i) Compare response rates between both treatment arms ii) Compare
overall survival between both treatment arms

Correlative objectives i) Investigate predictive biomarkers of response in blood and archived
tumor tissue ii) Investigate mechanisms of resistance for palbociclib in blood and tumor
tissue

Inclusion Criteria:

1. Be informed of the investigational nature of the study and all pertinent aspects of
the trial

2. Sign and provide written consent in accordance with institutional and federal
guidelines.

3. ECOG Performance status of 0-2

4. Recurrent or metastatic HER2-positive breast cancer (HER2 positive is defined per
ASCO-CAP guidelines)

5. Adequate cardiac reserve (EF≥50%)

6. Serum creatinine ≤ 1.5 x institutional upper limit of normal (IULN), bilirubin ≤ 2.0,
and an SGOT/SGPT/alkaline phosphatase ≤ 2.0 x IULN

7. Adequate bone marrow function (ANC ≥1000, Platelets ≥100,000/ml, Hemoglobin ≥10gm/dL)

8. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests
and other trial procedures

9. Been treated with pertuzumab previously (neoadjuvant or metastatic setting). Patients
who weren't able to tolerate pertuzumab due to side effects can be eligible for study
upon discussion with the study PI

10. No more than 2 lines of therapy in the metastatic disease setting

Exclusion Criteria:

1. HER2 negative tumors

2. Prior treatment with T-DM1

3. Prior treatment with CDK 4/6 inhibitors

4. Known active CNS metastases or carcinomatous meningitis. Patients with stable CNS
metastases including brain metastases who have completed a course of radiotherapy are
eligible for the study provided they are clinically stable. However, oral
corticosteroids for control of CNS symptoms are not allowed on study

5. Known documented or suspected hypersensitivity to the components of the study drug(s)
or analogs.

6. Uncontrolled systemic illness, including but not limited to ongoing or active
infection

7. Symptomatic congestive heart failure, unstable angina pectoris, stroke or myocardial
infarction within 3 months

8. Be pregnant or breast feeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female subjects with reproductive potential must have a negative
pregnancy test (serum or urine) prior to enrollment and must agree to use effective
contraception during the period of therapy

9. Concurrent hormonal or other anti-neoplastic therapy is not allowed. Patients can
receive supportive therapy like bone-directed therapy including bisphosphonates or
denosumab