Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer

NCT02947685 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 1 other identifier: AFT-38
• Study Type: interventional
• Target: 518
• Locations: 8 countries
• Sites: 106

Brief Summary

The primary objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy alone in improving the outcomes of subjects with hormone receptor-positive, HER2+ metastatic breast cancer.

Conditions

HER-2 Positive Breast Cancer; Estrogen Receptor Positive Breast Cancer

Keywords

breast cancer; malignant tumor of the breast; HER2+; HR+; metastatic breast cancer

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival (PFS) as Assessed by Investigator

  The time from registration to disease progression or death.

  7 years 3 months

Secondary Outcomes (8)

• Overall Survival (OS)

  7 years 3 months

• 3 and 5 Year Survival Probabilities

  5 years

• Objective Response Rate (OR: CR or PR)

  24 months

• Duration of Response (DOR)

  72 months

• Clinical Benefit Rate

  24 months

Other Outcomes (3)

• Trough Plasma Concentration of Palbociclib, Trastuzumab and Pertuzumab

  Palbociclib PK assessment: Day 22, Cycle 1, No; Pertuzumab, Trastuzumab PK assessment: Day 1, Cycle 4

• PIK3CA Genotype Assessed in Circulating cfDNA

  Day 1, Cycle 1, Day 1, Cycle 4, End of Treatment, approx 24 months

• Tumor Tissue Biomarkers Including Genes, Proteins, and RNA Expression

  Baseline

Study Arms (2)

Arm A

EXPERIMENTAL

Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression

Drug: palbociclib; Drug: trastuzumab; Drug: pertuzumab; Drug: letrozole; Drug: Anastrozole; Drug: Exemestane; Drug: Fulvestrant

Arm B

ACTIVE COMPARATOR

AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression

Drug: pertuzumab; Drug: letrozole; Drug: Anastrozole; Drug: Exemestane; Drug: Fulvestrant

Interventions

palbociclib DRUG

o Starting dose: 125 mg capsule taken orally once per day for 21 days followed by 7 days off to complete 28 day cycle. Dose reductions: 100 mg, 75 mg. allowed. Number of Cycles: until progression or unacceptable toxicity develops

Also known as: Ibrance

Arm A

trastuzumab DRUG

Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib. Trastuzumab dosing will be determined based on a loading dose of 8mg trastuzumab/kg body weight for Q3WK dosing schedules or a maintenance dose of 6mg/kg trastuzumab/kg dosing weight for Q3WK dosing schedules. Loading dose will be administered on Cycle 1, Day 1.

Also known as: Herceptin

Arm A

pertuzumab DRUG

Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib.Pertuzumab will be administered at a loading dose of 840 mg infusion and then at a maintenance dose of 420 mg q3wks. If patient is within 5 weeks of receiving loading dose at Cycle 1, Day 1, patient may start with maintenance dose of 420 mg.

Also known as: Perjeta

Arm A; Arm B

letrozole DRUG

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for letrozole oral therapy is 2.5 mg orally, once a day.

Also known as: Femara

Arm A; Arm B

Anastrozole DRUG

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for anastrozole is 1 mg orally, once a day.

Also known as: Arimidex

Arm A; Arm B

Exemestane DRUG

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for exemestane is 25 mg orally, once a day.

Also known as: Aromasin

Arm A; Arm B

Fulvestrant DRUG

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for Fulvestrant is 250 mg injections on Day 1 and Day 15 of Cycle 1, and q4weeks thereafter.

Also known as: Faslodex

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures
• Age ≥18 years (or per national guidelines)
• Patients must have histologically confirmed invasive breast cancer that is metastatic or not amenable for resection or radiation therapy with curative intent. Histological documentation of metastatic/recurrent breast cancer is not required if there is unequivocal evidence for recurrence of the breast cancer.
• Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+ and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.
• Patients must agree to provide a representative formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) from primary breast or metastatic site (archival) OR at least 15 freshly cut unstained slides from such a block, along with a pathology report documenting HER2 positivity and hormone receptor positivity.
• Patients should be willing to provide a representative tumor specimen obtained from recently biopsied metastatic disease if clinically feasible. This is recommended but optional tissue.
• Signed Main Informed Consent Form obtained prior to any study specific assessments and procedures
• Age ≥ 18 years (or per national guidelines)
• ECOG performance status 0-1
• Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
• Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into the study must use adequate contraception for the duration of protocol treatment which is 6 months after the last treatment with palbociclib if they are in Arm A and for 7 months after last treatment with trastuzumab if in either Arm A or Arm B Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository).
• Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy regimen to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion) 12 weeks between last dose of chemotherapy-anti-HER2therapy and randomization are allowed. Endocrine therapy could start before study randomization.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
• Prior Treatment Specifics
• Patients may or may not have received neo/adjuvant therapy, but must have a disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months.

You may not qualify if:

• Concurrent therapy with other Investigational Products.
• Prior therapy with any CDK 4/6 inhibitor.
• History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization (see Section 8.6.3 for list of strong inhibitors or inducers of CYP3A isoenzymes).
• Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
• Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
• Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
• QTc interval \>480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
• Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis

Sponsors & Collaborators

• Alliance Foundation Trials, LLC.: lead
• Pfizer: collaborator
• GBG Forschungs GmbH: collaborator
• Fondazione Michelangelo: collaborator
• PrECOG, LLC.: collaborator
• Breast Cancer Trials, Australia and New Zealand: collaborator
• Syneos Health: collaborator
• SOLTI Breast Cancer Research Group: collaborator
• UNICANCER: collaborator

Study Sites (106)

UCSF

San Francisco, California, 94115, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

Baycare Healthcare (Morton Plant Mease)

Clearwater, Florida, 33756, United States

Location

Memorial Healthcare System

Hollywood, Florida, 33021, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Florida Hospital

Orlando, Florida, 32804, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

Ingalls Memorial Hospital

Harvey, Illinois, 60426, United States

Location

Cancer Center of Kansas

Wichita, Kansas, 67214, United States

Location

Ochsner Medical Center Jefferson

New Orleans, Louisiana, 70121, United States

Location

New England Cancer Specialists

Scarborough, Maine, 04074, United States

Location

University of Maryland - Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Lowell General Hospital

Lowell, Massachusetts, 01854, United States

Location

Michigan Cancer Research Consortium (St. Joseph Mercy Hospital

Ann Arbor, Michigan, 48106, United States

Location

West Michigan Cancer Center

Grand Rapids, Michigan, 49503, United States

Location

Metro-Minnesota NCI Community Oncology Research Program

Minneapolis, Minnesota, 55416, United States

Location

Mayo Clinic, Rochester, MN

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Hackensack Medical Center

Hackensack, New Jersey, 07601, United States

Location

The Valley Hospital, Okonite Research Center

Paramus, New Jersey, 07652, United States

Location

New Mexico Cancer Care Alliance

Albuquerque, New Mexico, 87131, United States

Location

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

First Health of the Carolinas Cancer Center

Pinehurst, North Carolina, 28374, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Legacy Good Samaritan Hospital

Portland, Oregon, 97210, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19106, United States

Location

Lexington Medical Center

West Columbia, South Carolina, 29169, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37204, United States

Location

MD Anderson

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah, 84112, United States

Location

Monash Health

Clayton, Australia

Location

St. Vincent's Hospital, Sydney Kinghorn Cancer Centre

Darlinghurst, Australia

Location

The Canberra Hospital

Garran, Australia

Location

Peter MacCallum Cancer Centre, Royal Melbourne Hospital

Melbourne, Australia

Location

Breast Cancer Research Centre-WA

Nedlands, Australia

Location

Icon Cancer Care

South Brisbane, Australia

Location

Mater Cancer Care Centre

South Brisbane, Australia

Location

Calvary Mater Newcastle Hospital

Waratah, Australia

Location

Westmead Hospital

Westmead, Australia

Location

Institut de Cancérologie de l'Ouest, site Paul Papin

Angers, France

Location

Institut Sainte Catherine

Avignon, France

Location

Institut Bergonié

Bordeaux, France

Location

Centre Francois Baclesse

Caen, France

Location

Centre Hospitalier Cholet

Cholet, France

Location

Centre Jean Perrin

Clermont-Ferrand, France

Location

Centre Georges François Leclerc

Dijon, France

Location

Centre Oscar Lambret

Lille, France

Location

CHU de Limoges

Limoges, France

Location

Centre Léon Bérard

Lyon, France

Location

Institut Paoli Calmettes

Marseille, France

Location

Institut de Cancerologie de Montpellier

Montpellier, France

Location

Centre Azureen de Cancerologie

Mougins, France

Location

Centre Antoine Lacassagne

Nice, France

Location

Institut Curie Site Paris

Paris, France

Location

Tenon Oncologie Médicale - APHP

Paris, France

Location

Centre CARIO-HPCA

Plérin, France

Location

Institut Jean Godinot

Reims, France

Location

Centre Eugene Marquis

Rennes, France

Location

Centre Henri Becquerel

Rouen, France

Location

Institut Curie Site Saint Cloud

Saint-Cloud, France

Location

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Intitut Claudius Regaud

Toulouse, France

Location

Gustave Roussy

Villejuif, France

Location

Marienhospital Bottrop

Bottrop, Germany

Location

St. Elisabeth Krankenhaus

Cologne, Germany

Location

Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH

Essen, Germany

Location

Agaplesion Markus Krankenhaus

Frankfurt, Germany

Location

Diakovere Henriettenstift Frauenklinik

Hanover, Germany

Location

UKSH, Klinik für Gynäkologie und Geburtshilfe

Kiel, Germany

Location

Praxis Prof. Nitz im Brustzentrum Niederrhein

Münster, Germany

Location

Universitätsklinikum Münster

Münster, Germany

Location

Leopoldina-Krankenhaus Schweinfurt

Schweinfurt, Germany

Location

Policlinico Sant'Orsola-Malpighi

Bologna, Italy

Location

U.O. Oncologia AOU Arcispedale Sant'Anna

Cona, Italy

Location

Istituto Europeo di Oncologia

Milan, Italy

Location

Ospedale San Raffaele

Segrate, Italy

Location

Ospedale Santa Maria della Misericordia

Udine, Italy

Location

Auckland City Hospital Cancer and Blood Research

Auckland, New Zealand

Location

Hospital Champalimaud

Lisbon, Portugal

Location

Hospital Da Luz

Lisbon, Portugal

Location

Hospital Beatriz Angelo

Loures, Portugal

Location

IPO Porto

Porto, Portugal

Location

Hospital Clínic de Barcelona

Barcelona, Spain

Location

Hospital General de Catalunya

Barcelona, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

ICO L'Hospitalet

Barcelona, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario de Fuenlabrada

Madrid, Spain

Location

Hospital Universitario Fundación Alcorcón

Madrid, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

MD Anderson Cancer Center Spain

Madrid, Spain

Location

Hospital Regional Universitario de Málaga

Málaga, Spain

Location

Hospital Universitario Virgen de la Arrixaca

Murcia, Spain

Location

Complejo Hospitalario de Navarra

Navarro, Spain

Location

Hospital Universitario de Salamanca

Salamanca, Spain

Location

Complejo Hospitalario Univ. De Santiago

Santiago, Spain

Location

Hospital Quirón Sagrado Corazón

Seville, Spain

Location

Hospital Sant Joan de Reus

Tarragona, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Spain

Location

Related Publications (40)

• Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012 Feb 4;379(9814):432-44. doi: 10.1016/S0140-6736(11)61625-5. Epub 2011 Dec 5.

  PMID: 22152853 BACKGROUND

• Welch HG, Gorski DH, Albertsen PC. Trends in Metastatic Breast and Prostate Cancer--Lessons in Cancer Dynamics. N Engl J Med. 2015 Oct 29;373(18):1685-7. doi: 10.1056/NEJMp1510443. No abstract available.

  PMID: 26510017 BACKGROUND

• Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.

  PMID: 22149875 BACKGROUND

• Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.

  PMID: 25693012 BACKGROUND

• Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr;49(6):1374-403. doi: 10.1016/j.ejca.2012.12.027. Epub 2013 Feb 26.

  PMID: 23485231 BACKGROUND

• Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999 Jun 15;13(12):1501-12. doi: 10.1101/gad.13.12.1501. No abstract available.

  PMID: 10385618 BACKGROUND

• van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993 Dec 24;262(5142):2050-4. doi: 10.1126/science.8266103.

  PMID: 8266103 BACKGROUND

• Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323-30. doi: 10.1016/0092-8674(95)90385-2. No abstract available.

  PMID: 7736585 BACKGROUND

• Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805-16. doi: 10.1016/0092-8674(93)90499-g.

  PMID: 8242751 BACKGROUND

• Koff A, Ohtsuki M, Polyak K, Roberts JM, Massague J. Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science. 1993 Apr 23;260(5107):536-9. doi: 10.1126/science.8475385.

  PMID: 8475385 BACKGROUND

• Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9-22. doi: 10.1101/gad.8.1.9.

  PMID: 8288131 BACKGROUND

• Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995 May;20(5):187-90. doi: 10.1016/s0968-0004(00)89005-2.

  PMID: 7610482 BACKGROUND

• Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67-74. doi: 10.1016/0092-8674(94)90573-8.

  PMID: 8033213 BACKGROUND

• Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503-6. doi: 10.1038/375503a0.

  PMID: 7777060 BACKGROUND

• Medema RH, Herrera RE, Lam F, Weinberg RA. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6289-93. doi: 10.1073/pnas.92.14.6289.

  PMID: 7603984 BACKGROUND

• Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK 3rd, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol. 2000 Jan;20(2):672-83. doi: 10.1128/MCB.20.2.672-683.2000.

  PMID: 10611246 BACKGROUND

• Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve RM, Hynes NE. ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol. 2000 May;20(9):3210-23. doi: 10.1128/MCB.20.9.3210-3223.2000.

  PMID: 10757805 BACKGROUND

• Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006 Jan;9(1):23-32. doi: 10.1016/j.ccr.2005.12.012.

  PMID: 16413469 BACKGROUND

• Nahta R, Iglehart JD, Kempkes B, Schmidt EV. Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy between herceptin and flavopiridol. Cancer Res. 2002 Apr 15;62(8):2267-71.

  PMID: 11956082 BACKGROUND

• Reddy HK, Mettus RV, Rane SG, Grana X, Litvin J, Reddy EP. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 2005 Nov 15;65(22):10174-8. doi: 10.1158/0008-5472.CAN-05-2639.

  PMID: 16288002 BACKGROUND

• Yang C, Ionescu-Tiba V, Burns K, Gadd M, Zukerberg L, Louis DN, Sgroi D, Schmidt EV. The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol. 2004 Mar;164(3):1031-8. doi: 10.1016/S0002-9440(10)63190-2.

  PMID: 14982856 BACKGROUND

• Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell. 2006 Jan;9(1):13-22. doi: 10.1016/j.ccr.2005.12.019.

  PMID: 16413468 BACKGROUND

• Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.

  PMID: 19874578 BACKGROUND

• Witkiewicz AK, Cox DW, Rivadeneira D, Ertel AE, Fortina P, Schwartz GF, Knudsen ES. The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer. Oncogene. 2014 Jul 24;33(30):3980-91. doi: 10.1038/onc.2013.367. Epub 2013 Oct 14.

  PMID: 24121271 BACKGROUND

• Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, Zamboni WC, Wong KK, Perou CM, Sharpless NE. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst. 2012 Mar 21;104(6):476-87. doi: 10.1093/jnci/djs002. Epub 2012 Feb 1.

  PMID: 22302033 BACKGROUND

• Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016 Mar 14;29(3):255-269. doi: 10.1016/j.ccell.2016.02.006.

  PMID: 26977878 BACKGROUND

• Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. Epub 2016 Mar 3.

  PMID: 26947331 BACKGROUND

• Ramakrishna N, Temin S, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, Giordano SH, Gonzalez-Angulo AM, Kirshner JJ, Krop I, Levinson J, Modi S, Patt DA, Perez EA, Perlmutter J, Winer EP, Lin NU. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014 Jul 1;32(19):2100-8. doi: 10.1200/JCO.2013.54.0955. Epub 2014 May 5.

  PMID: 24799487 BACKGROUND

• Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL, Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, Gelmon K, Giordano SH, Gligorov J, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver SD, Nordstrom EB, Pagani O, Partridge A, Penault-Llorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C, Van't Veer L, Vorobiof D, Vrieling C, West N, Xu B, Winer E. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)dagger. Ann Oncol. 2014 Oct;25(10):1871-1888. doi: 10.1093/annonc/mdu385. Epub 2014 Sep 18. No abstract available.

  PMID: 25234545 BACKGROUND

• Lipton A, Ali SM, Leitzel K, Demers L, Harvey HA, Chaudri-Ross HA, Brady C, Wyld P, Carney W. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol. 2003 May 15;21(10):1967-72. doi: 10.1200/JCO.2003.09.098.

  PMID: 12743150 BACKGROUND

• Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, Friedlander RJ Jr, Gargiulo J, Strenger R, Vogel CL, Ryan PD, Ellis MJ, Nunes RA, Bunnell CA, Campos SM, Hallor M, Gelman R, Winer EP. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol. 2003 Aug 1;21(15):2889-95. doi: 10.1200/JCO.2003.02.018.

  PMID: 12885806 BACKGROUND

• Chan A, Martin M, Untch M, Gil MG, Guillem-Porta V, Wojtukiewicz M, Kellokumpu-Lehtinen P, Sommer HL, Georgoulias V, Battelli N, Pawlicki M, Aubert D, Bourlard T, Gasmi J, Villanova G, Petruzelka L; Navelbine Herceptin Project. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. Br J Cancer. 2006 Oct 9;95(7):788-93. doi: 10.1038/sj.bjc.6603351. Epub 2006 Sep 12.

  PMID: 16969343 BACKGROUND

• Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, Deasy S, Cobleigh M, Shiomoto G. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol. 1997 Mar;15(3):974-86. doi: 10.1200/JCO.1997.15.3.974.

  PMID: 9060536 BACKGROUND

• EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990 Dec;16(3):199-208. doi: 10.1016/0168-8510(90)90421-9.

  PMID: 10109801 BACKGROUND

• 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.

  PMID: 25524798 RESULT

• Finn, R.S., et al., PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). ASCO Meeting Abstracts, 2016. 34(15_suppl): p. 507.

  RESULT

• Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP, Piccart M; European Organization for the Research and Treatment of Cancer (EORTC)- Investigational Drug Branch for Breast Cancer (IDBBC). Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol. 2003 Sep;14(9):1391-8. doi: 10.1093/annonc/mdg362.

  PMID: 12954578 RESULT

• Pfizer, Inc. Palbociclib (PD-0332991): Investigator's Brochure. N.p.: Pfizer, 2015. Print.

  RESULT

• Metzger O, Mandrekar S, Goel S, Gligorov J, Lim E, Ciruelos E, Loibl S, Dockter T, Gonzalez Farre X, Francis PA, Lynce F, Lanzillotti J, DuFrane C, Wall A, Strand C, Krop I, Vaz-Luis I, Tripathy D, Loi S, Prat A, Goetz M, Escriva-de-Romani S, Porter D, Spoenlein J, Stover DG, Sardesai S, Heudel P, Koehler M, Huang Bartlett C, Holynskyj A, Gopalakrishna P, Gauthier E, Delaloge S, Miller K, Winer EP, Gianni L, Partridge AH, DeMichele A, Carey LA. Palbociclib for Hormone-Receptor-Positive, HER2-Positive Advanced Breast Cancer. N Engl J Med. 2026 Jan 29;394(5):451-462. doi: 10.1056/NEJMoa2511218.

  PMID: 41604639 DERIVED

• Peddi PF, Slamon DJ. Frontiers in HER2-positive breast cancer in 2020. Curr Opin Obstet Gynecol. 2021 Feb 1;33(1):48-52. doi: 10.1097/GCO.0000000000000677.

  PMID: 33369581 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib; Trastuzumab; pertuzumab; Letrozole; Anastrozole; exemestane; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Matthew Goetz
• Organization: Mayo Clinic

goetz.matthew@mayo.edu

507-293-0526

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2016
• First Posted: October 28, 2016
• Study Start: June 21, 2017
• Primary Completion: October 15, 2024
• Study Completion (Estimated): July 31, 2026
• Last Updated: February 12, 2026
• Results First Posted: February 12, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (25); NZ (1); IT (5); DE (9); ES (18); US (35); PT (4); AU (9)