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

NCT ID: NCT02536742

Last Updated: 2024-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 124 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-30
• Study Completion Date: 2022-12-22

Brief 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.

Detailed 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.

Conditions

Metastatic Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental

Palbociclib plus Fulvestrant

Group Type: EXPERIMENTAL

Palbociclib

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

PD-0332991; Ibrance; Faslodex

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Breast International Group

OTHER

Sponsor Role: collaborator

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Luca Malorni, MD PhD

Role: STUDY_CHAIR

USL4 Hospital of Prato, Italy

Locations

Sint-Augustinus

Antwerp, , Belgium

Institut Jules Bodet

Brussels, , Belgium

Cliniques Universitaires Saint-Luc

Brussels, , Belgium

Antwerp University Hospital

Edegem, , Belgium

UZ Leuven

Leuven, , Belgium

CHU Liege

Liège, , Belgium

Clinique St. Elizabeth

Namur, , Belgium

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

Milan, , Italy

Istituti Clinici Scientifici Maugeri, Medical Oncology Unit

Pavia, , Italy

Azienda USL4 Prato

Prato, , Italy

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, , United Kingdom

Countries

Belgium; Italy; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 20453888 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25524798 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26030518 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22547606 (View on PubMed)

Malorni L, Tyekucheva S, Hilbers FS, Ignatiadis M, Neven P, Colleoni M, Henry S, Ballestrero A, Bonetti A, Jerusalem G, Papadimitriou K, Bernardo A, Seles E, Duhoux FP, MacPherson IR, Thomson A, Davies DM, Bergqvist M, Migliaccio I, Gebhart G, Zoppoli G, Bliss JM, Benelli M, McCartney A, Kammler R, De Swert H, Ruepp B, Fumagalli D, Maibach R, Cameron D, Loi S, Piccart M, Regan MM; International Breast Cancer Study Group; Breast International Group and PYTHIA Collaborators. Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant. Eur J Cancer. 2022 Mar;164:39-51. doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13.

Reference Type: DERIVED

PMID: 35172272 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.ibcsg.org

Sponsor

Other Identifiers

2014-005387-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

WI198393

Identifier Type: OTHER

Identifier Source: secondary_id

IBCSG 53-14 / BIG 14-04

Identifier Type: -

Identifier Source: org_study_id