PATRICIA is a phase II, open-label, multicentre, Simon's two-stage-design study of the
combination of palbociclib plus trastuzumab, with or without letrozole, in post-menopausal
patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who have
received chemotherapy and treatment with trastuzumab for their metastatic disease. Cohorts A,
B1, and B2 based on their HR status and treatment allocation were planned.
Cohort A included patients with hormone receptor-negative, HER2 positive breast cancer, who
received trastuzumab + palbociclib.
Cohort B1 included patients with hormone receptor-positive, HER2 positive breast cancer, who
received trastuzumab + palbociclib.
Cohort B2 included patients with hormone receptor-positive, HER2 positive breast cancer, who
received trastuzumab + palbociclib + letrozole.
The aim of the PATRICIA study is to test the hypothesis that the addition of Palbociclib to
standard therapy is well tolerated and can provide a benefit in progression-free survival.
Based on interim results from this trial that support the benefit of CDK4 / 6 inhibition in
luminal disease, two additional cohorts will be included.
After the amendment of PATRICIA study, two additional cohorts will be included:
- Cohort C1: will include patients with OR+, HER2 positive, Luminal intrinsic subtype
determined by PAM50 who will receive trastuzumab + palbociclib + endocrine therapy (ET)
- Cohort C2: will include patients with OR+, HER2 positive, Luminal intrinsic subtype
determined by PAM50 who will receive treatment of physician's choice.
When the recruitment of those cohorts C begins, the recruitment in cohorts A and B will be
closed.
For cohorts C, an adaptive design will be applied to compare arms of treatment in patients
with Luminal subtype locally advanced or metastatic breast cancer (MBC).
All patients in those cohorts will have histologically- confirmed HR+/HER2-positive and
PAM50-confirmed Luminal intrinsic subtype breast adenocarcinoma, and must have received at
least 1 (and no more than 4) previous lines of anti-HER2 regimens for locally advanced
disease or MBC (including prior treatment with a taxane, trastuzumab and Antibody-Drug
conjugate).
Stratification factors will include number of previous regimens for advanced breast cancer
(one and two vs three and four) and presence of visceral disease (yes vs no).
Treatment in all cohorts will be administered until progression, unacceptable toxicity,
patient consent withdrawal, or death 516 patients will be screened and a total of 232
patients will be included. The inclusion period will be divided in two phases. During phase I
it is planned to include 60 patients in 24 months; considering early stopping rule according
to SF rate. During phase II, the trial will continue until the final evaluable number of
patients are included.
Inclusion Criteria
For Cohorts A and B
1. Written signed Informed Consent for all study procedures in accordance with the local
administrative requirements prior to starting the protocol-specific procedures.
2. Female patients
3. Age 18 years or older
4. ECOG performance status 0 or 1.
5. Invasive HER2 positive breast cancer, according to the local laboratory, defined
according to ASCO/CAP criteria as:
1. 3+ overexpression on immunohistochemistry (>10% of invasive tumor cells with
intensive, circumferential membrane staining)
2. Positive in situ hybridization (FISH/CISH/SISH) in >10% of invasive tumor cells,
having counted at least 20 cells in the area and based on:
i. Single-probe HER2 gene copy number ≥ 6 signals/cell. ii. Dual-probe HER2/CEP17
ratio ≥ 2.0 with a mean HER2 gene copy number ≥ 4.0 signals/cell; HER2/CEP17 ratio ≥
2.0 and < 4.0 signals/cell; and HER2/CEP17 ratio < 2.0 and ≥ 6.0 signals/cell.
6. Known hormone receptor, determined locally according to ASCO/CAP guidelines; OR or PgR
considered positive in case of ≥1% of cell nuclei positive.
7. Histologically-confirmed adenocarcinoma of the breast, metastatic or locally advanced.
1. Patients with locally advanced disease must have recurrent or progressive disease
unsuitable for resection with curative intent. Patients with standard curative
options available will not be eligible.
2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated
in both sites or in a metastatic biopsy.
8. All patients must have received at least 2 (maximum 4) previous lines of systemic
treatment for metastatic or locally advanced disease, at least one of which must have
included trastuzumab. Previous use of other anti-HER2 treatment, alone or in
combination with chemotherapy, is permitted, including lapatinib, neratinib,
pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted.
9. Tumour tissue available for biomarker analysis, obtained from metastatic lesions
(preferably) or from the primary tumor.
10. Measurable or non-measurable (but evaluable) disease according to RECIST v1.1
criteria. (Appendix 5).
11. Adequate organ function, defined as:
1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
2. Haemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).
3. Platelets > 100,000/mm3.
4. Creatinine ≤ 1.5 x normal value
5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis).
6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN
only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.
7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient
has Gilbert's syndrome).
12. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic
ventriculography (MUGA).
13. Absence of psychological, family, sociological or geographical conditions that could
potentially hinder compliance with the study protocol and follow-up schedule. These
situations must be discussed with the patient before she is included in the study.
..14. Postmenopausal status defined as previous bilateral oophorectomy, age >60 or
<60, and amenorrhoea for at least 12 months (in absence of chemotherapy, tamoxifen,
toremifene or ovarian suppression) and FSH and estradiol in postmenopausal range,
according to local laboratory.
For cohorts C:
1. Written signed Informed Consent for all study procedures in accordance with the local
administrative requirements prior to starting the protocol-specific procedures.
2. Male or female patients. Premenopausal or postmenopausal women.
3. Age 18 years or older.
4. ECOG performance status 0 to 2 (Appendix 1).
5. Invasive HER2 positive breast cancer, according to the central laboratory, defined
according to ASCO/CAP criteria (Wolff et al. Arch Pathol Lab Med 2018;)
6. Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines;
OR or PgR considered positive in case of ≥1% of cell nuclei positive.
7. Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or
Luminal B).
8. Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced.
1. Patients with locally advanced disease must have recurrent or progressive disease
unsuitable for resection with curative intent. Patients with standard curative
options available will not be eligible.
2. In patients with bilateral breast cancer, HER2+ positivity must be demonstrated
in both sites or in a metastatic biopsy.
9. All patients must have received at least 1(maximum 4) previous lines of systemic
treatment for metastatic or locally advanced disease, at least one of which must have
included trastuzumab. Previous use of other anti-HER2 treatment, alone or in
combination with chemotherapy, is permitted, including lapatinib, neratinib,
pertuzumab or T-DM1. Previous use of any chemotherapy or hormone agent is permitted.
10. Tumour tissue available for biomarker analysis, obtained from metastatic lesions
(preferably) or from the primary tumour.
11. Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria
(Appendix 5).
12. Adequate organ function, defined as:
1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
2. Hemoglobin (Hb) ≥9 g/dl (transfusion or use of EPO is permitted).
3. Platelets > 100,000/mm3
4. Creatinine ≤ 1.5 x normal value
5. AST or ALT ≤ 2.5 x ULN (or ≤5 x ULN in case of liver metastasis)
6. Alkaline phosphatase ≤2.5 x ULN. Alkaline phosphatase may be more than 2.5 x ULN
only in the case of bone metastases, and AST and ALT less than 1.5 x ULN.
7. Total bilirubin ≤1.5 mg/dl (higher bilirubin levels are permitted if the patient
has Gilbert's syndrome).
13. Baseline LVEF ≥50% measured using echocardiogram or equilibrium isotopic
ventriculography (MUGA).
14. Absence of psychological, family, sociological or geographical conditions that could
potentially hinder compliance with the study protocol and follow-up schedule. These
situations must be discussed with the patient before she is included in the study.
15. If female of childbearing potential, must have a negative result of serum pregnancy
test performed within 7 days prior to the first dose of study treatment.
16. Participants with a history of treated 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 CNS-directed therapy
and the screening radiographic study.
- No history of intracranial hemorrhage or spinal cord hemorrhage.
- Stable doses or no need of corticosteroids and anti-convulsants for symptomatic
control
- Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 of
study treatment; and recovery from any significant (Grade ≥ 3) acute toxicity
Exclusion criteria
For cohorts A, B and C
1. Treatment with any investigational anticancer drug within 14 days of the start of
study treatment.
2. Patient has received more than 4 previous lines of treatment (anti-HER2 drug +/-
chemotherapy) for metastatic breast cancer or locally advanced disease. Exclusively
hormonal treatments will not be taken into account.
3. Previous treatment with a cyclin-dependent kinase inhibitor.
4. History of other malignant tumours in the past 5 years, with the exception of
adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the
skin, uterine cancer in stage I or other malignant tumours with an expected curative
outcome.
5. Radiation therapy for metastases outside the brain carried out in the 21 days prior to
inclusion in the study and/or patients who have received radiation to > 30% of the
bone marrow.
6. Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 21 days
prior to inclusion in the study. Biphosphonates will be permitted for the prevention
of bone events.
7. History of exposure to cumulative anthracycline doses greater than follows:
1. Adriamycin > 400 mg/m2
2. Epirubicin > 720 mg/m2
3. Mitoxantrone > 120 mg/m2
4. Idarubicin > 90 mg/m2
5. If another anthracycline or more than one anthracycline has been used, the
cumulative dose must not exceed the equivalent of 400 mg/m2 of adriamycin.
8. Cardiopulmonary dysfunction, defined as:
1. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg)
despite optimum medical treatment.
2. Angina pectoris or arrhythmia poorly controlled with optimum medical treatment.
3. History of congestive heart failure NCI CTCAE version 4.0 grade ≥ 3 NYHA class ≥
2.
4. History of LVEF decrease to < 40% or symptomatic congestive heart failure during
prior treatment with trastuzumab.
5. Myocardial infarction within 6 months before randomisation.
6. Resting dyspnoea due to complications of the malignant disease, requiring
continuous oxygen therapy.
9. Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or
haematological disorder, wound healing disorders, ulcers, bone fractures, infectious
processes).
10. Major surgery in the 28 days prior to randomisation or foreseeable during study
treatment period.
11. Infection with HIV or active Hepatitis B and/or Hepatitis C.
12. History of trastuzumab intolerance, including grade 3-4 infusion reaction or
hypersensitivity.
13. Known hypersensitivity to any of the study drugs, including inactive ingredients.
14. Inability, in the opinion of the investigator, to comply with the protocol
requirements or any comorbidity that might hinder study follow-up, response evaluation
or the informed consent process.
