Phase II Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib

The primary objectives are to compare progression-free survival (PFS) in in fulvestrant plus
palbociclib and tamoxifen plus palbociclib arms in patients unselected by ESR1 mutation, and
in the subset of patients with ESR1-mt tumors assessed primarily from ctDNA at enrollment.

Patients with ER+ breast cancer who had 2 to 3 prior lines of endocrine therapy and up to one
line of chemotherapy for MBC, excluding fulvestrant and tamoxifen, will be randomized in a
1:1 ratio to receive fulvestrant 500mg IM Q28 days with one extra dose on D15 of the first
cycle (as a loading dose) plus palbociclib125mg/day PO on a 21 days on/7 days off schedule or
tamoxifen 20mg PO daily plus palbociclib125mg/day PO on a 21 days on/7 days off schedule .

For inclusion in the study subjects should fulfill the following criteria:

1. Signed informed consent

2. Patients must have histologically or cytologically confirmed invasive breast cancer
that is ER+ (>1% staining) with radiographical or clinical evidence of metastatic
disease

a. Measurable and/or non-measurable disease

3. Prior therapies:

1. Patients must have previously received an aromatase inhibitor in the adjuvant,
neo-adjuvant or metastatic setting.

2. Patients must have previously received palbociclib in the adjuvant, neo-adjuvant
or metastatic setting.

3. The minimum duration of AI in the adjuvant setting is 2 years.

4. There is no minimum duration of AI in the metastatic setting or neoadjuvant
setting.

5. Patients may have been previously treated with an mTOR inhibitor or other
investigational agent in addition to an aromatase inhibitor.

6. Prior treatment with tamoxifen is allowed in the adjuvant setting provided that
it was followed by a minimum of 2 years of an AI.

4. Brain metastasis is allowed if previously treated, stable and off steroids for a
minimum of 56 days

5. Age > 18 years

6. Male or female breast cancer is allowed

7. Patients may be pre- or post-menopausal; pre-menopausal patients must be on ovarian
suppression and must be adequately suppressed on LHRH agonists with estradiol levels
in the post-menopausal range

a. Premenopausal patients cannot be pregnant and must agree to adequate birth control
in addition to ovarian suppression. Agreement by the patient and/or partner to use
highly effective, nonhormonal form of contraception or two effective forms of
non-hormonal contraception. Contraception use should continue during the duration of
study treatment and for at least 6 months after the last dose of study treatment.

8. ECOG performance status 0-2

9. Adequate bone marrow function as indicated by the following, within 14 days of
enrollment:

1. ANC ≥ 1500 cells/mm3

2. Platelets ≥ 100,000 cells/ mm3

3. Hemoglobin ≥ 9 g/dL

10. Adequate liver function, as indicated by the following, within 14 days of enrollment.

1. Total bilirubin 1.5upper limit of normal (ULN)

2. AST 1.5 X ULN

3. ALT ≤ 2.5X ULN

4. Alkaline phosphatase ≤ 2.5X ULN with the following exception; ALP ≤ 5X ULN in
patients with bone metastases.

11. Adequate hemostatic function as determined by PT, INR and aPTT < 1.5X ULN (unless on
therapeutic coagulation, in which case the adequate level of anticoagulation will be
determined by the investigator).

12. Adequate renal function, as indicated by creatinine ≤ 1.5X ULN. Subjects should not
enter the study if any of the following exclusion criteria are fulfilled

1. Prior therapy exclusions:

a. Prior therapy with fulvestrant b. Prior therapy with tamoxifen in the metastatic setting
c. More than 3 prior lines of endocrine therapy in the metastatic setting d. More than one
prior line of chemotherapy in the metastatic setting 2. Washout of 2 weeks is required for
aromatase inhibitors; washout of 4 weeks is required for, everolimus or other biological
agents.

3. Patients must not be receiving any other investigational agent. 4. Patients with
symptomatic, untreated CNS metastases are not eligible. 5. Patients may not have
significant concurrent illness, infection, pregnancy or lactation 6. Patients must not have
a different active malignancy, except for skin basal cell carcinoma, skin squamous cell
carcinoma and cervical intraepithelial neoplasia.