Palbociclib in Molecularly Characterized ER-positive/HER2-negative Metastatic Breast Cancer

Metastatic Breast Cancer Clinical Trial

— PYTHIA  

Official title:

A Phase II Study of Palbociclib Plus Fulvestrant for Pretreated Patients With ER+/HER2- Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02536742
• Other study ID #: IBCSG 53-14 / BIG 14-04
• Secondary ID: 2014-005387-15WI
• Status: Completed
• Phase: Phase 2
• Start date: August 30, 2016
• Est. completion date: December 22, 2022

Study information

• Verified date: July 2023
• Source: ETOP IBCSG Partners Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This international, multicenter, prospective single arm Phase II biomarker discovery clinical trial with the primary objective of assessing the association of PFS with gene mutations, gene copy number aberrations and gene signatures in post-menopausal women with hormone receptor positive, HER2-negative metastatic or locally relapsed breast cancer whose disease has progressed after prior adjuvant endocrine therapy or one line systemic treatment, i.e., endocrine treatment or chemotherapy, administered for metastatic disease.

Description:

Patients will be treated with the combination of palbociclib and fulvestrant. The primary objective is to assess the association of the primary endpoint progression-free survival (PFS) with potential markers. The trial is included in the AURORA program conducted by the Breast International Group (BIG), an international study aiming to collect and characterize biological samples, including metastatic tissue, from patients with advanced breast cancer. The primary aim of the PYTHIA study is to discover potentially innovative biomarkers for the selection of patients to Palbociclib/Fulvestrant treatment. The strength of the trial lies in its conduct in conjunction with the AURORA study, which systematically evaluates a panel of biomarkers in tissue and blood, in a certified central lab. Stemming from this association, an abundance of molecular profiling information will become available for different biological samples. Additional molecular and functional imaging assessments performed within the context of the PYTHIA study increase its scientific merit, since it will represent a prospective, systematic effort to identify biomarkers for patient stratification, integrating several molecular profiling assessments.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• Est. completion date: December 22, 2022
• Est. primary completion date: August 28, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Female gender
• Age = 18 years
• Postmenopausal, defined as women with:
• Prior bilateral surgical oophorectomy; or
• Amenorrhea and age = 60 years; or
• Age < 60 years and amenorrhea for 12 or more consecutive months in the absence of alternative pathological or physiological cause and FSH and serum estradiol levels within the laboratory's reference ranges for postmenopausal women.
• Endocrine resistant disease, defined as one of:
• Relapse while on adjuvant endocrine therapy;
• Relapse within 12 months after completion of adjuvant endocrine therapy;
• Progression of disease under first line endocrine therapy for metastatic and/or loco-regionally advanced breast cancer. Note: Patient may have received one prior chemotherapy for advanced or metastatic breast cancer.
• ER positive tumor and HER2-negative tumor, as assessed locally
• ECOG Performance Status 0-1.
• Measurable or non-measurable but evaluable disease according to RECIST 1.1.
• Written Informed Consent (IC) for screening procedures.
• Written informed consent to participate in the AURORA program of BIG.
• The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
• Life expectancy >3 months.
• Hematological status:
• Absolute neutrophil count = 1.5 × 109/L
• Platelet count = 100 × 109/L
• Hemoglobin = 9 g/dL
• Hepatic status:
• Serum total bilirubin = 1.5 × upper limit of normal (ULN).
• AST and ALT = 2.5 × ULN; if the patient has liver metastases, ALT and AST must be = 5 × ULN.
• Glucose in normal range, or well-controlled diabetes defined as an HbA1c level = 7.5%.
• Renal status:
• Creatinine = 1.5 ×ULN or creatinine clearance > 60 ml/min.
• International Normalized Ratio (INR) or Prothrombin Time (PT) =1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant.
• Ability to swallow oral medication.

Exclusion Criteria:

• Prior use of fulvestrant or any CDK inhibitor.
• More than one prior line of chemotherapy for metastatic or locally relapsed disease.
• Previous or current non-breast malignancies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin.
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
• Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade =2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (NYHA functional classification =3), cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
• QTc exceeding 480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
• Uncontrolled electrolyte disorders that can reinforce the QT-prolonging effect of the drug (e.g., hypocalcemia, hypokalemia, hypomag¬nesemia).
• Known history of HIV seropositivity. HIV screening is not required at baseline.
• Uncontrolled diabetes defined as HbA1c level > 7.5%.
• Concurrent disease or familial, sociological or geographical condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient's safety.
• Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent.
• Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant.
• Treatment with an investigational agent in the 4 weeks before enrollment.
• Concurrent treatment with any of the drugs not permitted
• Adverse events (except alopecia) from previous systemic cancer therapy, radiotherapy or surgery have not recovered to CTCAE v4.0 grade 1 or resolved prior to enrollment.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Palbociclib
125 mg, orally, daily for 3 weeks followed by 1 week off; repeated at every 28 days cycle until progression, lack of tolerability, or patient declines further protocol treatment.
• Fulvestrant
500mg, intramuscularly on days 1 and 15 of cycle 1, then on day 1 (+/- 3 days) of every 28 days cycle until progression, lack of tolerability, or patient declines further protocol treatment.

Locations

Country	Name	City	State
Belgium	Sint-Augustinus	Antwerpen
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Institut Jules Bodet	Brussels
Belgium	Antwerp University Hospital	Edegem
Belgium	UZ Leuven	Leuven
Belgium	CHU Liege	Liège
Belgium	Clinique St. Elizabeth	Namur
Italy	Ospedali degli Infermi, S.O.C. Oncologia	Biella
Italy	Ospedale Centrale Bolzano, Medical Oncology	Bolzano
Italy	IRCCS San Martino University Hospital	Genova
Italy	Mater Salutis Hospital AULSS 21 della Regione Veneto	Legnago
Italy	Istituto Europeo di Oncologia	Milano
Italy	Istituti Clinici Scientifici Maugeri, Medical Oncology Unit	Pavia
Italy	Azienda USL4 Prato	Prato
United Kingdom	Velindre NHS Trust	Cardiff
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Singleton Hospital	Swansea
United Kingdom	Royal Cornwall	Truro

Sponsors (2)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation	Breast International Group

Countries where clinical trial is conducted

Belgium,  Italy,  United Kingdom, 

References & Publications (4)

Di Leo A, Malorni L. Polyendocrine treatment in estrogen receptor-positive breast cancer: a "FACT" yet to be proven. J Clin Oncol. 2012 Jun 1;30(16):1897-900. doi: 10.1200/JCO.2012.41.7394. Epub 2012 Apr 30. No abstract available. — View Citation

Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub 2014 Dec 16. — View Citation

Mittendorf EA, Liu Y, Tucker SL, McKenzie T, Qiao N, Akli S, Biernacka A, Liu Y, Meijer L, Keyomarsi K, Hunt KK. A novel interaction between HER2/neu and cyclin E in breast cancer. Oncogene. 2010 Jul 8;29(27):3896-907. doi: 10.1038/onc.2010.151. Epub 2010 May 10. — View Citation

Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With and Without Progression Free Survival (PFS) Events	Time from treatment initiation until documented disease progression according to RECIST 1.1 or death, whichever occurs first	Maximum 36 months
Secondary	Best Overall Response	Best overall response is based on RECIST (Response evaluation criteria in solid tumors) 1.1 criteria and is defined as best response recorded from enrollment across all time points until disease progression. Confirmation of partial response (PR) or complete response (CR) by an additional scan was not requested in this trial (rationale: initially because of randomized placebo-controlled design; subsequently because no hypothesis testing of progression-free survival, PFS, distribution relative to an historical control).	From date of enrolment until patient's end of treatment visit (or a maximum of 12 months after EoT in the absence of tumor progression), assessed up to 48 months.
Secondary	Best Overall Response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD)	Disease control is defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) (or non-CR/non-PD, progressive disease, in the case of non-measurable disease only) lasting for at least 24 weeks, measured from enrollment until first documentation of progressive disease	From date of enrolment until patient's end of treatment visit (or a maximum of 12 months after EoT in the absence of tumor progression), assessed up to 48 months.

External Links

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