"Neo-Adjuvant Treatment With Palbociclib: Effect on Ki67 and Apoptosis Before, During and After Treatment "

NCT02530424 | Completed Phase 2 DMC

• 1 other identifier: FM-14-B01
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 7

Brief Summary

This is a multicenter neoadjuvant trial conducted under the sponsorship and overall trial management of the Fondazione Michelangelo in Italy. Women with a diagnosis of invasive unilateral non metastatic ER-positive breast cancer expressing HER2 and suitable for neoadjuvant therapy Patients in this study will receive: Trastuzumab+Pertuzumab+Palbociclib with or without Fulvestrant (HPPF) Trastuzumab 8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations) Pertuzumab 840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations) Palbociclib 125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles) Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6) The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab Definitive surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination reported above After completion of the neoadjuvant and surgical treatment patients will receive irradiation as locally acceptable. Patients will also continue to receive systemic drug therapy including chemotherapy (plus standard anti-HER2 treatment until completion of full 1 year if HER2 3+ or neu amplified, i.e. cohorts A and B) and endocrine therapy according to local guidelines at the Investigator's discretion.

Conditions

Breast Neoplasms

Keywords

HER2-positive; ER-positive; invasive; CDK4,6; Palbociclib; neoadjuvant treatment

Outcome Measures

Primary Outcomes (2)

• Serial measures of Ki67

  Changes in Ki67 scores from baseline before therapy, 2 weeks after and then at surgery

  Participants will be followed for the duration of protocol therapy, an expected average of 26 weeks

• Serial measures of apoptosis

  Changes in apoptosis biomarker scores from baseline before therapy and at surgery

  Participants will be followed for the duration of protocol therapy, an expected average of 26 weeks

Secondary Outcomes (3)

• pathological complete response (pCR)

  at surgery

• clinical objective response

  Participants will be followed for the duration of medical therapy, an expected average of 24 weeks

• Number of participants with adverse events as a Measure of Safety and Tolerability

  Participants will be followed for up to 7 months

Study Arms (1)

Trast-pert-palbo-fulve

EXPERIMENTAL

Patients will receive an association of drugs (trastuzumab, pertuzumab, palbociclib plus or minus fulvestrant) as neoadjuvant chemotherapy. Definitive surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination. After completion of surgical treatment patients will receive irradiation as locally acceptable.

Drug: Trastuzumab; Drug: Pertuzumab; Drug: Palbociclib; Drug: Fulvestrant

Interventions

Trastuzumab DRUG

Trastuzumab (8 mg/kg loading dose IV, then 6 mg/kg IV) will be given on day 1 q. 3 weeks for a total of 6 administrations

Also known as: Herceptin

Trast-pert-palbo-fulve

Pertuzumab DRUG

Pertuzumab (840 mg as an i.v. infusion) will be given on day 1 q. 3 weeks for a total of 6 administration

Also known as: Perjeta

Trast-pert-palbo-fulve

Palbociclib DRUG

Palbociclib will be given at the dose of 125 mg po q.d. x 21 every 4 weeks (i.e. 1 week rest period for a total of 5 cycles

Also known as: Ibrabce

Trast-pert-palbo-fulve

Fulvestrant DRUG

Fulvestrant will be administered according to local prescription guidelines and will be given intra-muscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose

Also known as: Faslodex

Trast-pert-palbo-fulve

Eligibility Criteria

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

You may qualify if:

• Female patients aged 18 years or older with tumors suitable for neoadjuvant treatment
• Early (\> 1.5 cm) or locally advanced untreated breast cancer
• Histologically confirmed invasive unilateral breast cancer
• HER2 status to be centrally confirmed (HER2 3+ of neu amplified for cohorts A and B; HER2 1+/2+ without amplification for cohort C)
• Positive estrogen receptor (ER) \> 10% and known progesterone receptor (PgR). Note: PgR assessment must be positive for cohort C
• Ki67 \> 20% for cohort C
• Available paraffin-embedded tumor block taken at diagnostic biopsy for central retrospective confirmation of HER2 and ER eligibility and for assessment of Ki67 value and apoptosis is mandatory
• All patients must agree to provide tumor tissues for centralized assessment of KI67 values and apoptosis at the required timelines (2 weeks from starting protocol therapy and at surgery)
• ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1
• Written informed consent to participate in the trial (approved by the Institutional Review Board/ Independent Ethics Committee) obtained prior to any study specific screening procedures
• Willing and able to comply with the protocol

You may not qualify if:

• Evidence of bilateral invasive breast cancer or metastatic disease (M1)
• Pregnant or lactating women.
• Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception
• Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy
• Previous extensive radiotherapy
• Previous investigational treatment for any condition within 4 weeks of registration date
• Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol
• Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results.
• Other serious illness or medical condition including: history of documented congestive cardiac failure; angina pectoris requiring anti-anginal medication; evidence of transmural infarction on ECG; poorly controlled hypertension; clinically significant valvular heart disease; high-risk uncontrolled arrhythmias
• Baseline left ventricular ejection fraction (LVEF) \< 55% by echocardiography or multi-gated scintigraphic scan (MUGA)
• QTc (corrected QT interval) \>480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)
• Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs
• Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus
• Current use or anticipated need for food or drugs that are known strong CYP3A4 (cytochrome P450 3A4) inhibitors or inducers
• Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia)

Sponsors & Collaborators

• Fondazione Michelangelo: lead

Study Sites (7)

Policlinico Sant'Orsola Malpighi

Bologna, BO, 40138, Italy

Location

Azienda Ospedaliero Universitaria di Ferrara - Arcispedale S. Anna

Ferrara, FE, 44124, Italy

Location

IST San Martino

Genova, GE, 16132, Italy

Location

Ospedale San Raffaele

Milan, MI, 20100, Italy

Location

Istituto Europeo di Oncologia

Milan, MI, 20141, Italy

Location

Arcispedale S.Maria Nuova A.O.Reggio Emilia

Reggio Emilia, RE, 42123, Italy

Location

Ospedale Santa Maria della Misericordia

Udine, UD, 33100, Italy

Location

Related Publications (3)

• Vigano L, Locatelli A, Ulisse A, Galbardi B, Dugo M, Tosi D, Tacchetti C, Daniele T, Gyorffy B, Sica L, Macchini M, Zambetti M, Zambelli S, Bianchini G, Gianni L. Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer. Clin Cancer Res. 2022 May 13;28(10):2167-2179. doi: 10.1158/1078-0432.CCR-21-3185.

  PMID: 35254385 DERIVED

• Gianni L, Colleoni M, Bisagni G, Mansutti M, Zamagni C, Del Mastro L, Zambelli S, Bianchini G, Frassoldati A, Maffeis I, Valagussa P, Viale G. Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer. NPJ Breast Cancer. 2022 Jan 10;8(1):1. doi: 10.1038/s41523-021-00377-8.

  PMID: 35013314 DERIVED

• Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P, Viale G. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018 Feb;19(2):249-256. doi: 10.1016/S1470-2045(18)30001-9. Epub 2018 Jan 8.

  PMID: 29326029 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Trastuzumab; pertuzumab; palbociclib; 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; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Luca Gianni, MD

  Ospedale San Raffaele

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 19, 2014
• First Posted: August 21, 2015
• Study Start: May 1, 2015
• Primary Completion: September 1, 2019
• Study Completion: November 1, 2019
• Last Updated: July 15, 2020

Record last verified: 2019-07

Locations

IT (7)