Study of Palbociclib and Trastuzumab With Endocrine Therapy in HER2-positive Metastatic Breast Cancer

  • STATUS
    Recruiting
  • End date
    Dec 25, 2021
  • participants needed
    232
  • sponsor
    SOLTI Breast Cancer Research Group
Updated on 25 January 2021
breast cancer
lapatinib
endocrine therapy
oophorectomy
metastasis
neutrophil count
hormone therapy
pertuzumab
liver metastasis
immunohistochemistry
tumor cells
HER2
primary tumor
biomarker analysis
trastuzumab
bone metastases
tamoxifen
adenocarcinoma
cish
palbociclib
breast adenocarcinoma
her2/neu-positive breast cancer
letrozole
chromogenic in situ hybridization

Summary

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.

Description

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.

Details
Condition Metastatic Breast Cancer, Stage IV Breast Cancer
Treatment Trastuzumab, Letrozole, Chemotherapy, Palbociclib, Endocrine Therapy, Antibody-Drug Conjugates
Clinical Study IdentifierNCT02448420
SponsorSOLTI Breast Cancer Research Group
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Are you female?
Do you have Metastatic Breast Cancer?
Do you have any of these conditions: Metastatic Breast Cancer or Stage IV Breast Cancer?
For Cohorts A and B
Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures
Female patients
Age 18 years or older
ECOG performance status 0 or 1
Invasive HER2 positive breast cancer, according to the local laboratory, defined according to ASCO/CAP criteria as
3+ overexpression on immunohistochemistry (>10% of invasive tumor cells with intensive, circumferential membrane staining)
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
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
Known hormone receptor, determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of 1% of cell nuclei positive
Histologically-confirmed adenocarcinoma of the breast, metastatic or locally advanced
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
In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy
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
Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumor
Measurable or non-measurable (but evaluable) disease according to RECIST v1.1 criteria. (Appendix 5)
Adequate organ function, defined as
Absolute neutrophil count (ANC) 1.5 x 109/L
Haemoglobin (Hb) 9 g/dl (transfusion or use of EPO is permitted)
Platelets > 100,000/mm3
Creatinine 1.5 x normal value
AST or ALT 2.5 x ULN (or 5 x ULN in case of liver metastasis)
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
Total bilirubin 1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome)
Baseline LVEF 50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA)
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
Written signed Informed Consent for all study procedures in accordance with the local administrative requirements prior to starting the protocol-specific procedures
Male or female patients. Premenopausal or postmenopausal women
Age 18 years or older
ECOG performance status 0 to 2 (Appendix 1)
Invasive HER2 positive breast cancer, according to the central laboratory, defined according to ASCO/CAP criteria (Wolff et al. Arch Pathol Lab Med 2018;)
Hormone receptor positive (HR+), determined locally according to ASCO/CAP guidelines; OR or PgR considered positive in case of 1% of cell nuclei positive
Centrally confirmed Luminal intrinsic subtype as per PAM50 analysis (i.e. Luminal A or Luminal B)
Histologically confirmed adenocarcinoma of the breast, metastatic or locally advanced
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
In patients with bilateral breast cancer, HER2+ positivity must be demonstrated in both sites or in a metastatic biopsy
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
Tumour tissue available for biomarker analysis, obtained from metastatic lesions (preferably) or from the primary tumour
Measurable or non-measurable (but evaluable) disease according to RECIST 1.1 criteria (Appendix 5)
Adequate organ function, defined as
Absolute neutrophil count (ANC) 1.5 x 109/L
Hemoglobin (Hb) 9 g/dl (transfusion or use of EPO is permitted)
Platelets > 100,000/mm3
Creatinine 1.5 x normal value
AST or ALT 2.5 x ULN (or 5 x ULN in case of liver metastasis)
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
Total bilirubin 1.5 mg/dl (higher bilirubin levels are permitted if the patient has Gilbert's syndrome)
Baseline LVEF 50% measured using echocardiogram or equilibrium isotopic ventriculography (MUGA)
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
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
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
Treatment with any investigational anticancer drug within 14 days of the start of study treatment
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
Previous treatment with a cyclin-dependent kinase inhibitor
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
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
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
History of exposure to cumulative anthracycline doses greater than follows
Adriamycin > 400 mg/m2
Epirubicin > 720 mg/m2
Mitoxantrone > 120 mg/m2
Idarubicin > 90 mg/m2
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
Cardiopulmonary dysfunction, defined as
Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) despite optimum medical treatment
Angina pectoris or arrhythmia poorly controlled with optimum medical treatment
History of congestive heart failure NCI CTCAE version 4.0 grade 3 NYHA class 2\
History of LVEF decrease to < 40% or symptomatic congestive heart failure during prior treatment with trastuzumab
Myocardial infarction within 6 months before randomisation
Resting dyspnoea due to complications of the malignant disease, requiring continuous oxygen therapy
Any other severe, uncontrolled disease (pulmonary, cardiac, metabolic, or haematological disorder, wound healing disorders, ulcers, bone fractures, infectious processes)
Major surgery in the 28 days prior to randomisation or foreseeable during study treatment period
Infection with HIV or active Hepatitis B and/or Hepatitis C
History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity
Known hypersensitivity to any of the study drugs, including inactive ingredients
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
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