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

HER-2 Positive Breast Cancer Clinical Trial

— PATINA  

Official title:

A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy After Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02947685
• Other study ID #: AFT-38
• Status: Active, not recruiting
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Breast Neoplasms
• Estrogen Receptor Positive Breast Cancer
• HER-2 Positive Breast Cancer

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, 

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* Note: There are 38 references in all — Click 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