Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02947685




Registration number
NCT02947685
Ethics application status
Date submitted
26/10/2016
Date registered
28/10/2016
Date last updated
19/09/2024

Titles & IDs
Public title
Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer
Scientific 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
Secondary ID [1] 0 0
AFT-38
Universal Trial Number (UTN)
Trial acronym
PATINA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HER-2 Positive Breast Cancer 0 0
Estrogen Receptor Positive Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - palbociclib
Treatment: Drugs - trastuzumab
Treatment: Drugs - pertuzumab
Treatment: Drugs - letrozole
Treatment: Drugs - Anastrozole
Treatment: Drugs - Exemestane
Treatment: Drugs - Fulvestrant

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

Active comparator: Arm B - AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression


Treatment: Drugs: 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

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free survival (PFS) as assessed by Investigator
Timepoint [1] 0 0
24 months
Secondary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
24 months
Secondary outcome [2] 0 0
3 and 5 year survival probabilities
Timepoint [2] 0 0
24 months
Secondary outcome [3] 0 0
Objective Response Rate (OR: CR or PR)
Timepoint [3] 0 0
24 months
Secondary outcome [4] 0 0
Duration of Response (DOR)
Timepoint [4] 0 0
24 months
Secondary outcome [5] 0 0
Clinical Benefit Rate (CBR: CR or PR or SD = 24 weeks
Timepoint [5] 0 0
24 months
Secondary outcome [6] 0 0
Safety: Type incidence and severity (as graded by NCI CTCAE v 4.0)
Timepoint [6] 0 0
24 months
Secondary outcome [7] 0 0
Patient Reported Outcomes
Timepoint [7] 0 0
24 months
Secondary outcome [8] 0 0
Incidence of CNS Metastasis
Timepoint [8] 0 0
24 months

Eligibility
Key inclusion criteria
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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/06/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/07/2026
Actual
Sample size
Target
496
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Monash Health - Clayton
Recruitment hospital [2] 0 0
St. Vincent's Hospital, Sydney Kinghorn Cancer Centre - Darlinghurst
Recruitment hospital [3] 0 0
The Canberra Hospital - Garran
Recruitment hospital [4] 0 0
Peter MacCallum Cancer Centre, Royal Melbourne Hospital - Melbourne
Recruitment hospital [5] 0 0
Breast Cancer Research Centre-WA - Nedlands
Recruitment hospital [6] 0 0
Icon Cancer Care - South Brisbane
Recruitment hospital [7] 0 0
Mater Cancer Care Centre - South Brisbane
Recruitment hospital [8] 0 0
Calvary Mater Newcastle Hospital - Waratah
Recruitment hospital [9] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
- Clayton
Recruitment postcode(s) [2] 0 0
- Darlinghurst
Recruitment postcode(s) [3] 0 0
- Garran
Recruitment postcode(s) [4] 0 0
- Melbourne
Recruitment postcode(s) [5] 0 0
- Nedlands
Recruitment postcode(s) [6] 0 0
- South Brisbane
Recruitment postcode(s) [7] 0 0
- Waratah
Recruitment postcode(s) [8] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Kansas
Country [7] 0 0
United States of America
State/province [7] 0 0
Louisiana
Country [8] 0 0
United States of America
State/province [8] 0 0
Maine
Country [9] 0 0
United States of America
State/province [9] 0 0
Maryland
Country [10] 0 0
United States of America
State/province [10] 0 0
Massachusetts
Country [11] 0 0
United States of America
State/province [11] 0 0
Michigan
Country [12] 0 0
United States of America
State/province [12] 0 0
Minnesota
Country [13] 0 0
United States of America
State/province [13] 0 0
Missouri
Country [14] 0 0
United States of America
State/province [14] 0 0
Nebraska
Country [15] 0 0
United States of America
State/province [15] 0 0
New Jersey
Country [16] 0 0
United States of America
State/province [16] 0 0
New Mexico
Country [17] 0 0
United States of America
State/province [17] 0 0
North Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Ohio
Country [19] 0 0
United States of America
State/province [19] 0 0
Oregon
Country [20] 0 0
United States of America
State/province [20] 0 0
Pennsylvania
Country [21] 0 0
United States of America
State/province [21] 0 0
South Carolina
Country [22] 0 0
United States of America
State/province [22] 0 0
Tennessee
Country [23] 0 0
United States of America
State/province [23] 0 0
Texas
Country [24] 0 0
United States of America
State/province [24] 0 0
Utah
Country [25] 0 0
France
State/province [25] 0 0
Angers
Country [26] 0 0
France
State/province [26] 0 0
Avignon
Country [27] 0 0
France
State/province [27] 0 0
Bordeaux
Country [28] 0 0
France
State/province [28] 0 0
Caen
Country [29] 0 0
France
State/province [29] 0 0
Cholet
Country [30] 0 0
France
State/province [30] 0 0
Clermont-Ferrand
Country [31] 0 0
France
State/province [31] 0 0
Dijon
Country [32] 0 0
France
State/province [32] 0 0
Lille
Country [33] 0 0
France
State/province [33] 0 0
Limoges
Country [34] 0 0
France
State/province [34] 0 0
Lyon
Country [35] 0 0
France
State/province [35] 0 0
Marseille
Country [36] 0 0
France
State/province [36] 0 0
Montpellier
Country [37] 0 0
France
State/province [37] 0 0
Mougins
Country [38] 0 0
France
State/province [38] 0 0
Nice
Country [39] 0 0
France
State/province [39] 0 0
Paris
Country [40] 0 0
France
State/province [40] 0 0
Plerin Cedex
Country [41] 0 0
France
State/province [41] 0 0
Reims
Country [42] 0 0
France
State/province [42] 0 0
Rennes
Country [43] 0 0
France
State/province [43] 0 0
Rouen
Country [44] 0 0
France
State/province [44] 0 0
Saint-Cloud
Country [45] 0 0
France
State/province [45] 0 0
Saint-Priest-en-Jarez
Country [46] 0 0
France
State/province [46] 0 0
Strasbourg
Country [47] 0 0
France
State/province [47] 0 0
Toulouse
Country [48] 0 0
France
State/province [48] 0 0
Villejuif
Country [49] 0 0
Germany
State/province [49] 0 0
Berlin
Country [50] 0 0
Germany
State/province [50] 0 0
Bielefeld
Country [51] 0 0
Germany
State/province [51] 0 0
Bottrop
Country [52] 0 0
Germany
State/province [52] 0 0
Düsseldorf
Country [53] 0 0
Germany
State/province [53] 0 0
Essen
Country [54] 0 0
Germany
State/province [54] 0 0
Frankfurt
Country [55] 0 0
Germany
State/province [55] 0 0
Hameln
Country [56] 0 0
Germany
State/province [56] 0 0
Hannover
Country [57] 0 0
Germany
State/province [57] 0 0
Karlsruhe
Country [58] 0 0
Germany
State/province [58] 0 0
Kiel
Country [59] 0 0
Germany
State/province [59] 0 0
Köln
Country [60] 0 0
Germany
State/province [60] 0 0
Munster
Country [61] 0 0
Germany
State/province [61] 0 0
Münster
Country [62] 0 0
Germany
State/province [62] 0 0
Oldenburg
Country [63] 0 0
Germany
State/province [63] 0 0
Schweinfurt
Country [64] 0 0
Germany
State/province [64] 0 0
Wiesbaden
Country [65] 0 0
Italy
State/province [65] 0 0
Bologna
Country [66] 0 0
Italy
State/province [66] 0 0
Cona
Country [67] 0 0
Italy
State/province [67] 0 0
Milano
Country [68] 0 0
Italy
State/province [68] 0 0
Segrate
Country [69] 0 0
Italy
State/province [69] 0 0
Udine
Country [70] 0 0
New Zealand
State/province [70] 0 0
Auckland
Country [71] 0 0
Portugal
State/province [71] 0 0
Lisboa
Country [72] 0 0
Portugal
State/province [72] 0 0
Loures
Country [73] 0 0
Portugal
State/province [73] 0 0
Porto
Country [74] 0 0
Spain
State/province [74] 0 0
Barcelona
Country [75] 0 0
Spain
State/province [75] 0 0
Madrid
Country [76] 0 0
Spain
State/province [76] 0 0
Murcia
Country [77] 0 0
Spain
State/province [77] 0 0
Málaga
Country [78] 0 0
Spain
State/province [78] 0 0
Navarro
Country [79] 0 0
Spain
State/province [79] 0 0
Salamanca
Country [80] 0 0
Spain
State/province [80] 0 0
Santiago
Country [81] 0 0
Spain
State/province [81] 0 0
Seville
Country [82] 0 0
Spain
State/province [82] 0 0
Tarragona
Country [83] 0 0
Spain
State/province [83] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Other
Name
Alliance Foundation Trials, LLC.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Pfizer
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
German Breast Group
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Fondazione Michelangelo
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
PrECOG, LLC.
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Breast Cancer Trials, Australia and New Zealand
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Syneos Health
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
SOLTI Breast Cancer Research Group
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
UNICANCER
Address [8] 0 0
Country [8] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT02947685
Trial related presentations / publications
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sherr CJ. D-type cyclins. Trends Biochem Sci. 1995 May;20(5):187-90. doi: 10.1016/s0968-0004(00)89005-2.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. Erratum In: Lancet Oncol. 2016 Apr;17(4):e136. doi: 10.1016/S1470-2045(16)00155-8. Lancet Oncol. 2016 Jul;17(7):e270. doi: 10.1016/S1470-2045(16)30222-4.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pfizer, Inc. Palbociclib (PD-0332991): Investigator's Brochure. N.p.: Pfizer, 2015. Print.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02947685