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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT02947685
Other study ID # AFT-38
Secondary ID
Status Active, not recruiting
Phase Phase 3
First received
Last updated
Start date June 21, 2017
Est. completion date July 31, 2026

Study information

Verified date June 2024
Source Alliance Foundation Trials, LLC.
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Description:

Subjects will be randomized into one of two treatment arms following minimum of 4 and maximum of 8 cycles of induction treatment with anti-HER2 therapy. Arm A subjects will receive the experimental therapy, palbociclib, in addition to their current anti-HER2 therapy and endocrine therapy. Arm B subjects will continue to receive the anti-HER2 therapy. It is expected that the addition of palbociclib to the first-line treatment of HER2 disease will delay the onset of therapeutic resistance and ultimately prolong the survival of patients with metastatic breast cancer. The study is designed to treat the subset of patients with HER2+ disease who are also hormone receptor positive (HR+). It is also expected that palbociclib will modulate the endocrine resistance in HER2+/HR+ disease and potentiate the benefits of anti-HER2 therapy. Lastly, the current study includes a comprehensive molecular characterization of the disease at study entrance which will allow us to investigate the benefits of palbociclib in subsets of HER2+/HR+ disease such as PIK3CA mutant.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 496
Est. completion date July 31, 2026
Est. primary completion date July 31, 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria (Preliminary Screening) 1. Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures 2. Age =18 years (or per national guidelines) 3. 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. 4. 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. 5. 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. 6. 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. Inclusion Criteria (Randomization Screening) 7. Signed Main Informed Consent Form obtained prior to any study specific assessments and procedures 8. Age = 18 years (or per national guidelines) 9. ECOG performance status 0-1 10. Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption. 11. 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). 12. 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. 13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Prior Treatment Specifics 14. 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. 15. Patients must have received an acceptable, standard, chemotherapy containing anti-HER2 based induction therapy for the treatment of metastatic breast cancer prior to study enrollment. For this study, chemotherapy is limited to a taxane or vinorelbine (only for trastuzumab-based regimen). Eligible patients are expected to have completed 6 cycles of chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 cycles of treatment is acceptable for patients experiencing significant toxicity associated with treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). The maximum number of cycles is 8. Patients can randomize immediately following completion of their induction therapy, or for those who have already completed induction, a gap of 12 weeks between their last infusion/dose of induction therapy and the C1D1 visit is permitted. Patients are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD). 16. Patients with a history or presence of asymptomatic 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 induction therapy and the screening radiographic study - No history of intracranial hemorrhage or spinal cord hemorrhage - Not requiring anti-convulsants for symptomatic control - Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade = 3) acute toxicity with no ongoing requirement for corticosteroid Baseline Body Function Specifics 17. Absolute neutrophil count = 1,000/mm3 18. Platelets = 100,000/mm3 19. Hemoglobin = 10g/dL 20. Total serum bilirubin = ULN; or total bilirubin = 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome. 21. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) = 3 × institutional ULN (=5 x ULN if liver metastases are present). 22. Serum creatinine below the upper limit of normal (ULN) of the institutional normal range or creatinine clearance = 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN. 23. Left ventricular ejection fraction (LVEF) = 50% at baseline as determined by either ECHO or MUGA Exclusion Criteria (Randomization) 1. Concurrent therapy with other Investigational Products. 2. Prior therapy with any CDK 4/6 inhibitor. 3. History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib. 4. 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). 5. 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. 6. 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. 7. 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. 8. QTc interval >480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes. 9. Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis

Study Design


Related Conditions & MeSH terms


Intervention

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

Locations

Country Name City State
Australia Monash Health Clayton
Australia St. Vincent's Hospital, Sydney Kinghorn Cancer Centre Darlinghurst
Australia The Canberra Hospital Garran
Australia Peter MacCallum Cancer Centre, Royal Melbourne Hospital Melbourne
Australia Breast Cancer Research Centre-WA Nedlands
Australia Icon Cancer Care South Brisbane
Australia Mater Cancer Care Centre South Brisbane
Australia Calvary Mater Newcastle Hospital Waratah
Australia Westmead Hospital Westmead
France Institut de Cancérologie de l'Ouest, site Paul Papin Angers
France Institut Sainte Catherine Avignon
France Institut Bergonié Bordeaux
France Centre Francois Baclesse Caen
France Centre Hospitalier Cholet Cholet
France Centre Jean Perrin Clermont-Ferrand
France Centre Georges François Leclerc Dijon
France Centre Oscar Lambret Lille
France CHU de Limoges Limoges
France Centre Léon Bérard Lyon
France Institut Paoli Calmettes Marseille
France Institut de Cancerologie de Montpellier Montpellier
France Centre Azureen de Cancerologie Mougins
France Centre Antoine Lacassagne Nice
France Hôpital Saint Louis Paris
France Institut Curie Site Paris Paris
France Tenon Oncologie Médicale - APHP Paris
France Centre CARIO-HPCA Plerin Cedex
France Institut Jean Godinot Reims
France Centre Eugene Marquis Rennes
France Centre Henri Becquerel Rouen
France Institut Curie Site Saint Cloud Saint-Cloud
France Institut de Cancérologie Lucien Neuwirth Saint-Priest-en-Jarez
France Centre Paul Strauss Strasbourg
France Intitut Claudius Regaud Toulouse
France Gustave Roussy Villejuif
Germany Praxisklinik Krebsheilkunde für Frauen Berlin
Germany Studiengesellschaft Onkologie Bielefeld Bielefeld
Germany Marienhospital Bottrop Bottrop
Germany Luisenkrankenhaus Düsseldorf Düsseldorf
Germany Universitätsklinikum Düsseldorf, Klinik für Frauenheilkunde & Geburtshilfe Düsseldorf
Germany Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH Essen
Germany Agaplesion Markus Krankenhaus Frankfurt
Germany Sana-Klinikum Hameln Hameln
Germany Diakovere Henriettenstift Frauenklinik Hannover
Germany Vidia Christliche Kliniken Karlsruhe Vincentius-Diakonissen-Kliniken gAG Frauenklinik Karlsruhe
Germany UKSH, Klinik für Gynäkologie und Geburtshilfe Kiel
Germany St. Elisabeth Krankenhaus Köln
Germany Praxis Prof. Nitz im Brustzentrum Niederrhein Munster
Germany Universitätsklinikum Münster Münster
Germany Univ. Klinikum Oldenburg AÖR Hämatologie/Onkologie Oldenburg
Germany Leopoldina-Krankenhaus Schweinfurt Schweinfurt
Germany HELIOS Dr. Horst Schmidt Kliniken Wiesbaden; Klinik für Gynäkologie und gynäkologische Onkologie Wiesbaden
Italy Policlinico Sant'Orsola-Malpighi Bologna
Italy U.O. Oncologia AOU Arcispedale Sant'Anna Cona
Italy Istituto Europeo di Oncologia Milano
Italy Ospedale San Raffaele Segrate
Italy Ospedale Santa Maria della Misericordia Udine
New Zealand Auckland City Hospital Cancer and Blood Research Auckland
Portugal Hospital Champalimaud Lisboa
Portugal Hospital Da Luz Lisboa
Portugal Hospital Beatriz Angelo Loures
Portugal IPO Porto Porto
Spain Hospital Clínic de Barcelona Barcelona
Spain Hospital General de Catalunya Barcelona
Spain Hospital Universitari Vall d'Hebron Barcelona
Spain ICO L'Hospitalet Barcelona
Spain Hospital Universitario 12 de Octubre Madrid
Spain Hospital Universitario de Fuenlabrada Madrid
Spain Hospital Universitario Fundación Alcorcón Madrid
Spain Hospital Universitario Fundación Jiménez Díaz Madrid
Spain Hospital Universitario La Paz Madrid
Spain Hospital Universitario Severo Ochoa Madrid
Spain MD Anderson Cancer Center Spain Madrid
Spain Hospital Regional Universitario de Málaga Málaga
Spain Hospital Universitario Virgen de la Arrixaca Murcia
Spain Complejo Hospitalario de Navarra Navarro
Spain Hospital Universitario de Salamanca Salamanca
Spain Complejo Hospitalario Univ. De Santiago Santiago
Spain Hospital Quirón Sagrado Corazón Seville
Spain Hospital Sant Joan de Reus Tarragona
Spain Hospital Clínico Universitario de Valencia Valencia
United States New Mexico Cancer Care Alliance Albuquerque New Mexico
United States Michigan Cancer Research Consortium (St. Joseph Mercy Hospital Ann Arbor Michigan
United States Anne Arundel Medical Center Annapolis Maryland
United States Emory University Atlanta Georgia
United States Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland
United States University of Maryland - Greenebaum Comprehensive Cancer Center Baltimore Maryland
United States Dana-Farber Cancer Institute Boston Massachusetts
United States The University of Chicago Medical Center Chicago Illinois
United States University of Illinois at Chicago Chicago Illinois
United States Baycare Healthcare (Morton Plant Mease) Clearwater Florida
United States Ohio State University Columbus Ohio
United States Duke Cancer Institute Durham North Carolina
United States West Michigan Cancer Center Grand Rapids Michigan
United States Hackensack Medical Center Hackensack New Jersey
United States Ingalls Memorial Hospital Harvey Illinois
United States Memorial Healthcare System Hollywood Florida
United States MD Anderson Houston Texas
United States Lowell General Hospital Lowell Massachusetts
United States University of Miami Miami Florida
United States Metro-Minnesota NCI Community Oncology Research Program Minneapolis Minnesota
United States Vanderbilt University Medical Center Nashville Tennessee
United States Ochsner Medical Center Jefferson New Orleans Louisiana
United States Nebraska Methodist Hospital Omaha Nebraska
United States University of Nebraska Medical Center Omaha Nebraska
United States Florida Hospital Orlando Florida
United States The Valley Hospital, Okonite Research Center Paramus New Jersey
United States University of Pennsylvania Philadelphia Pennsylvania
United States First Health of the Carolinas Cancer Center Pinehurst North Carolina
United States Legacy Good Samaritan Hospital Portland Oregon
United States Mayo Clinic, Rochester, MN Rochester Minnesota
United States Washington University School of Medicine Saint Louis Missouri
United States Huntsman Cancer Institute, University of Utah Salt Lake City Utah
United States UCSF San Francisco California
United States New England Cancer Specialists Scarborough Maine
United States Georgetown University Medical Center Washington District of Columbia
United States Lexington Medical Center West Columbia South Carolina
United States Cancer Center of Kansas Wichita Kansas

Sponsors (9)

Lead Sponsor Collaborator
Alliance Foundation Trials, LLC. Breast Cancer Trials, Australia and New Zealand, Fondazione Michelangelo, German Breast Group, Pfizer, PrECOG, LLC., SOLTI Breast Cancer Research Group, Syneos Health, UNICANCER

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  New Zealand,  Portugal,  Spain, 

References & Publications (38)

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* Note: There are 38 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Other Trough Plasma concentration of palbociclib, trastuzumab and pertuzumab only for patients enrolled in the US Palbociclib PK assessment: Day 22, Cycle 1, No; Pertuzumab, Trastuzumab PK assessment: Day 1, Cycle 4
Other PIK3CA genotype assessed in circulating cfDNA Progression Free Survival (PFS) based upon investigator assessment of progression between patients in the two treatment arms in the subset of patients with tumors bearing a PIK3CA mutation. Day 1, Cycle 1, Day 1, Cycle 4, End of Treatment, approx 24 months
Other Tumor tissue biomarkers including genes, proteins, and RNA expression Will evaluate baseline tumor and blood-based markers as predictors of benefit from the addition of palbociclib to anti-HER2 therapy plus endocrine therapy Baseline
Primary Progression-free survival (PFS) as assessed by Investigator 24 months
Secondary Overall Survival (OS) Defined as time from date of randomization to date of death due to any cause 24 months
Secondary 3 and 5 year survival probabilities Survival probabilities will be estimated using the Kaplan-Meier method 24 months
Secondary Objective Response Rate (OR: CR or PR) Defined as complete response (CR) or partial response (PR) according to RECIST v1.1 24 months
Secondary Duration of Response (DOR) Defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or to death from any cause, whichever occurs first 24 months
Secondary Clinical Benefit Rate (CBR: CR or PR or SD = 24 weeks The Clinical Benefit Rate (CBR) on each treatment arm will be estimated by dividing the number of patients with CR, PR, or SD/Non-CR and Non-PD (for patients with measurable disease) = 24 weeks by the number of patients randomized to the treatment arm. 24 months
Secondary Safety: Type incidence and severity (as graded by NCI CTCAE v 4.0) Seriousness and attribution to the study medications of AEs and any laboratory abnormalities 24 months
Secondary Patient Reported Outcomes Time to symptom progression (FACT-B PFB-TOI), breast cancer specific health treatment related quality of life and general health status 24 months
Secondary Incidence of CNS Metastasis Compare the incidence of CNS metastasis between treatment arms 24 months
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