This is a randomized, 2-arm, open-label, multicenter, international phase II trial. A total
of 196 patients will be included.
The study will include patients with metastatic Hormone Receptor positive / Human Epidermal
Growth Factor Receptor (HER2) negative breast cancer with progressive disease after endocrine
Patients will be randomized (1:1) between two treatment arms: A. palbociclib + fulvestrant
and b. capecitabine.
1. Women 18 years or older.
2. Postmenopausal, defined by at least one of the following criteria:
1. Prior bilateral oophorectomy
2. Age ≥60
3. Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the
postmenopausal range according to the local laboratory reference. Note: For women
with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are
needed to ensure postmenopausal status. OR Pre/perimenopausal if treated with
goserelin that was initiated at least 4 weeks prior to randomization.
3. Locally advanced or metastatic breast cancer deemed not amenable to curative surgery
or curative radiation therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Known estrogen-receptor positive and/or progesterone receptor positive breast cancer
reported by local laboratory.
6. Known HER2-negative breast cancer defined as a negative in situ hybridization test or
an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH,
CISH, or SISH) test is required by local laboratory testing.
7. Documented resistance to endocrine therapy (tamoxifen or aromatase inhibitors) defined
1. Recurrence while on or within 12 months after the end of adjuvant endocrine
2. Progression while on or within 1 month after the end of endocrine treatment for
8. Previous chemotherapy for breast cancer including an anthracycline and a taxane (only
one line for metastatic disease) is permitted.
9. Radiological or other objective evidence (eg. new skin lesions or new lymph node
lesions) of recurrence during or after the most recent systemic therapy for recurrent
/ metastatic disease prior to randomization.
10. At least one tumor lesion accessible for biopsy that is a non-bone lesion or a
predominantly lytic bone lesion, and that measures at least 10 mm in largest diameter.
This lesion must not have been treated previously with irradiation (although the area
may have been irradiated before the occurrence of the lesion).
11. Patient is interested to participate in the trial, including the obligatory biopsies
at a metastatic site/site before the start of study treatment.
12. Clinically and/or radiographically documented measurable disease according to RECIST
v1.1 criteria or bone-only disease with at least one predominantly lytic or mixed bone
lesion. For measurable disease, at least one site of disease must have largest tumor
diameter of at least:
1. 10 mm if measured by CT-scan, ultrasound, or physical exam
2. 20 mm if measured by Chest X-ray
3. 15 mm if suspiciously enlarged lymph node (short axis) see Eisenhauer et al. for
more details All radiology studies must be performed within 28 days prior to
registration (35 days if negative).
13. Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7
days prior to enrollment:
1. Hematology: Absolute granulocytes > 1.5 x 109/L, Platelets > 100 x 109/L
2. Biochemistry: Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum creatinine ≤
1.5 x ULN.
14. 14. APTT and INR ≤ 1.5 x ULN or institution accepted values for biopsy within 7 days
prior to enrollment.
15. Signed written informed consent provided by the patient.
1. Previous treatment with a CDK4/6 inhibitor, mTOR or PI3K inhibitor, fulvestrant or
capecitabine. Short-term (<28 days) exposure to mTOR or PI3K inhibitor in the
(neo)adjuvant setting is allowed.
2. More than one prior chemotherapy lines for metastatic breast cancer. Previous
(neo)adjuvant chemotherapy or for radically treated local or regional relapse is
allowed in addition to one prior chemotherapy line for metastatic breast cancer Note:
A chemotherapy line in advanced disease is an anticancer regimen that contains at
least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic
chemotherapy regimen was discontinued for a reason other than disease progression and
the decision for its discontinuation was taken within 21 days after starting it, then
this regimen does not count as a "prior line of chemotherapy". Chemotherapy regimens
composed of more than one drug are considered as one line of therapy.
3. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash,
sclerotic bone etc).
4. CNS metastases unless asymptomatic and adequately controlled with surgery or
radiotherapy. Stable CNS disease is defined as CNS metastases or cord compression that
have been definitively treated and the patient is clinically stable off
anticonvulsants and steroids for at least 4 weeks before randomization.
5. Leptomeningeal carcinomatosis
6. Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening
complications in the short term.
7. Concurrent malignancy of any site, except adequately controlled limited basal cell
carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in
situ of the cervix.
8. Active cardiac disease or a history of cardiac dysfunction including any of the
1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction
within 12 months prior to study entry
2. History of documented congestive heart failure (New York Heart Association
functional classification III-IV)
3. Documented cardiomyopathy
4. QTc > 480 msec as measured by Bazett's formula, family or personal history of
long or short QT syndrome, Brugada syndrome or known history of QTc prolongation
or Torsade de Pointes.
5. Uncontrolled hypertension.
9. Patients being treated with drugs recognized as strong inhibitors or inducers of the
isoenzyme CYP3A (including, but not limited, to - see table 6 - Rifabutin, Rifampicin,
Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin)
continuously for at least 7 days during any time period in the last 2 weeks prior to
10. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous
severe reactions to a fluoropyrimidine.
11. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment
with anticoagulants that preclude intramuscular administration of drugs.
12. Ongoing pregnancy or lactation.
13. Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule; those conditions
should be discussed with the patient before registration in the trial.
14. A previous metastatic tumor biopsy reported to be negative for both estrogen receptor
and progesterone receptor (i.e. <1% for both), or positive for HER2 status (amplified