Palbociclib for HR Positive / HER2-negative Isolated Locoregional Recurrence of Breast Cancer

NCT ID: NCT03820830

Last Updated: 2025-03-07

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 405 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-27
• Study Completion Date: 2029-01-01

Brief Summary

POLAR is a phase III clinical trial, which will test the safety and efficacy of an investigational combination of drugs to learn whether the combination of drugs works for a specific cancer. Palbociclib (Ibrance®) is the name of the investigational agent, which is assessed together with standard anti-hormone therapy in this study. Palbociclib is used to treat patients with hormone receptor-positive / HER2-negative breast cancer which has spread beyond the original tumor and/or to other organs.

During this study, anti-hormone therapy will consist of either a selective estrogen receptor modulator (such as tamoxifen) or an aromatase inhibitor (anastrozole, letrozole, exemestane) or fulvestrant (Faslodex®). Premenopausal women and men may also receive a drug called an LHRH (luteinizing hormone-releasing hormone) agonist by injection.

It is standard of care for people with hormone receptor positive breast cancer to take anti-hormone therapy. The study doctor will determine the type of standard anti-hormone therapy that will be given during this trial.

The purpose of the POLAR study is to compare the effect of using 3 years of palbociclib in combination with standard anti-hormone therapy with standard anti-hormone therapy alone and to evaluate the time until the breast cancer returns, if it does return.

Detailed Description

Local or regional recurrence of breast cancer after mastectomy or lumpectomy indicates a poor prognosis, and accompanies or precedes distant metastasis in a high proportion of patients. Patients with isolated locoregional recurrences (ILRR), without evidence of distant metastasis hold a substantial risk of developing subsequent distant metastasis, with 5-year survival probabilities ranging between 45% and 80% after locoregional recurrence. These outcomes show the powerful negative prognostic importance of ILRR events and the need for treatments beyond surgical removal of the ILRR.

Adjuvant chemotherapy and endocrine therapies reduce the risk of relapse and death in patients with primary breast cancer. However, few data are available to inform the recommendation of systemic treatment for locoregional recurrence.

The International Breast Cancer Studies Group carried out the CALOR trial, Chemotherapy as Adjuvant for Locally Recurrent breast cancer (IBCSG 27-02 / BIG 1-02 / NSABP B-37), in collaboration with the Breast International Group (BIG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP), to establish whether chemotherapy improves the outcome of patients with ILRR. An updated, final analysis of CALOR after median follow-up of about 9 years was published in the Journal of Clinical Oncology in April 2018, which confirmed chemotherapy benefitted patients with resected ER-negative ILRR and did not support the use of chemotherapy for ER-positive ILRR.

CALOR results strongly suggest that tailoring treatment according to the disease characteristics of the recurrent lesion, in this case ILRR, provides a better indication of the possible responsiveness to treatment than relying on the characteristics of the primary tumor.

Palbociclib has been granted FDA approval in the U.S. for the treatment of HR-positive/HER2-negative advanced breast cancer in combination with the hormonal treatments letrozole and fulvestrant given the unprecedented results in terms of efficacy of two pivotal clinical trials (PALOMA-2 and PALOMA-3). Palbociclib and other CDK4/6 inhibitors have also shown a good toxicity profile and therefore are ideal candidates for combination with hormonal therapy. CDK4/6 pathway activation is a well-known mechanism of resistance to endocrine therapy, indeed CDK4/6 inhibitors have shown activity in cellular models of acquired resistance to endocrine therapies.

The reason for prolonged duration of palbociclib in the adjuvant setting (2 years) comes from the evidence of preclinical studies where cell senescence was investigated as an appealing mechanism of cell death and was indeed observed in vitro after exposure of breast cancer cells and tumors to a combination of endocrine therapy and palbociclib. It is therefore hypothesized that the longer patients receive combined treatment with palbociclib and an antiestrogen, the more likely they may derive prolonged clinical benefit.

Based on the results of the CALOR trial and on strong evidence of activity of the combination of CDK4/6 inhibitors and endocrine therapy, the hypothesis of the POLAR trial is that the CDK4/6 inhibitor palbociclib in combination with endocrine therapy may be active as adjuvant therapy in patients with HR-positive/HER2-negative resected isolated locoregional recurrence of breast cancer.

Conditions

Breast Cancer Recurrent

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Palbociclib plus standard endocrine therapy

Palbociclib 125 mg/day tablet taken orally for 21 days, followed by 7 days rest for 3 years from randomization, plus standard endocrine therapy for at least 3 years from randomization.

Group Type: EXPERIMENTAL

Palbociclib 125mg

Intervention Type: DRUG

Palbociclib 125 mg oral tablet taken daily for 3 years from randomization

Standard endocrine therapy

Intervention Type: DRUG

Aromatase inhibitor (anastrozole or exemestane or letrozole) oral daily tablet, or Selective Estrogen Receptor Modulator (SERM) such as tamoxifen oral daily tablet or fulvestrant (Faslodex) injection once every 2 weeks for 3 doses then every month. Premenopausal women and men may also receive an LHRH (luteinizing hormone-releasing hormone) agonist by injection. Standard endocrine therapy will be given for at least 3 years from randomization.

Standard endocrine therapy

Aromatase inhibitor (anastrozole or exemestane or letrozole) oral daily tablet, or Selective Estrogen Receptor Modulator (SERM) such as tamoxifen oral daily tablet or fulvestrant (Faslodex) injection once every 2 weeks for 3 doses then every month. Premenopausal women and men may also receive an LHRH (luteinizing hormone-releasing hormone) agonist by injection. Standard endocrine therapy will be given for at least 3 years from randomization.

Group Type: ACTIVE_COMPARATOR

Standard endocrine therapy

Intervention Type: DRUG

Aromatase inhibitor (anastrozole or exemestane or letrozole) oral daily tablet, or Selective Estrogen Receptor Modulator (SERM) such as tamoxifen oral daily tablet or fulvestrant (Faslodex) injection once every 2 weeks for 3 doses then every month. Premenopausal women and men may also receive an LHRH (luteinizing hormone-releasing hormone) agonist by injection. Standard endocrine therapy will be given for at least 3 years from randomization.

Interventions

Palbociclib 125mg

Palbociclib 125 mg oral tablet taken daily for 3 years from randomization

Intervention Type: DRUG

Standard endocrine therapy

Aromatase inhibitor (anastrozole or exemestane or letrozole) oral daily tablet, or Selective Estrogen Receptor Modulator (SERM) such as tamoxifen oral daily tablet or fulvestrant (Faslodex) injection once every 2 weeks for 3 doses then every month. Premenopausal women and men may also receive an LHRH (luteinizing hormone-releasing hormone) agonist by injection. Standard endocrine therapy will be given for at least 3 years from randomization.

Intervention Type: DRUG

Other Intervention Names

Ibrance; PD-0332991

Eligibility Criteria

Inclusion Criteria

1. Histologically confirmed invasive breast cancer, defined as first proven ipsilateral local and/or regional recurrence of a primary invasive breast cancer in at least one of these sites:

• breast;
• the chest wall including mastectomy scar and/or skin;
• axillary or internal mammary lymph nodes.

2. Completion of locoregional therapy:

• completion of gross excision of recurrence within 6 months prior to randomization;
• completion of radiotherapy (if given) more than 2 weeks prior to randomization

3. Negative or microscopically involved margins

4. Female or male aged 18 years or older

5. ECOG performance status 0 or 1

6. Recurrent tumor must be hormone receptor positive: ER+ and/or PgR+ ≥1% by IHC

7. Recurrent tumor must be HER2-negative (0, 1+, 2+ by IHC and/or ISH/FISH not amplified).Tumor with HER2 status 2+ by IHC must also be negative (not amplified) by ISH/FISH

8.-10. Normal hematological, renal, and liver function 11. The patient agrees to make tumor (diagnostic core biopsy or surgical specimen of ipsilateral isolated locoregional recurrence) available for submission for central pathology review 12. Patients must either be planned to initiate, or have already started, endocrine therapy for ipsilateral isolated locoregional recurrence 13.) Written Informed Consent prior to randomization

Exclusion Criteria

1. Recurrence of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules) not surgically removable

2. Evidence of distant metastasis as based on conventional staging examinations (physical, chest X-ray or CT, abdominal ultrasound or CT, bone scintigraphy or FDG-PET-CT).

3. Bilateral synchronous or metachronous invasive breast cancer (in situ carcinoma of the contralateral breast is allowed)

4. Inflammatory breast cancer

5. Patients with a history of malignancy, other than invasive breast cancer, with the following exceptions:

• Patients diagnosed, treated and disease-free for at least 5 years and deemed by the investigator to be at low risk for recurrence of that malignancy are eligible.
• Patients with the following malignancies are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast; cervical cancer in situ; thyroid cancer in situ; non-metastatic, non-melanomatous skin cancers.

6. Previous treatment with palbociclib or any other CDK 4/6 inhibitors

7. Previous or planned chemotherapy or planned radiotherapy for the ipsilateral isolated locoregional recurrence (radiotherapy is allowed, but must be completed more than 2 weeks prior to randomization)

8. Concurrent disease or condition that would make the patient inappropriate for study participation or any serious medical disorder that would interfere with the patient's safety

9. Pregnant or lactating women; lactation has to stop before randomization

10. Patients with psychiatric illness/social situations that would limit compliance with study requirements

11. Contraindications or known hypersensitivity to the palbociclib or excipients

12. History of extensive disseminated/bilateral or known presence of interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is not considered an exclusion criterion.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elisabetta Munzone, MD

Role: STUDY_CHAIR

European Institute of Oncology

Locations

Medizinische Universität Graz (MUG)

Graz, , Austria

Medizinische Universität Innsbruck - Univ.-Klinik f. Frauenheilkunde

Innsbruck, , Austria

Uniklinikum Salzburg

Salzburg, , Austria

MUW - Universitätsklinik für Innere Medizin

Vienna, , Austria

Institut Sainte Catherine

Avignon, , France

Institut Bergonie

Bordeaux, , France

Polyclinique Bordeaux Nord

Bordeaux, , France

Centre Francois Baclesse

Caen, , France

Cêntre Hospitaler de Cholet

Cholet, , France

Centre Georges François Leclerc

Dijon, , France

Centre Hospitalier Universitaire de Limoges

Limoges, , France

Groupe hospitalier de Bretagne Sud, Hôpital du Scorff

Lorient, , France

Centre Leon Berard

Lyon, , France

ICM Val d'Aurelle

Montpellier, , France

Centre Antoine Lacassagne

Nice, , France

Centre Paul Strauss

Strasbourg, , France

Institut Claudius Regaud

Toulouse, , France

Gustave Roussy

Villejuif, , France

National Institute of Oncology

Budapest, , Hungary

Cro Irccs

Aviano, , Italy

ASST Papa Giovanni XXIII

Bergamo, , Italy

PO Antonio Perrino Brindisi

Brindisi, , Italy

Istituto scientifico Romagnolo per lo studio e la cura

Meldola, , Italy

Istituto Europeo di Oncologia

Milan, , Italy

AOU Maggiore Della Carita, University of Eastern Piedmont

Novara, , Italy

Azienda Ospedaliero-Universitaria di Parma

Parma, , Italy

Istituti Clinici Scientifici Maugeri

Pavia, , Italy

Ospedale S. Stefano

Prato, , Italy

U.O. Oncologia, Ospedale Infermi

Rimini, , Italy

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Tenerife, Spain

Hospital Universitario de La Coruña

A Coruña, , Spain

Hospital General Universitario de Alicante

Alicante, , Spain

Hospital Universitario Vall d´Hebrón

Barcelona, , Spain

Instituto Catalan de Oncologia L´Hospitalet

Barcelona, , Spain

Hospital de Basurto

Bilbao, , Spain

Institut Català d´Oncología (ICO)

Girona, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

HU Ramón y Cajal

Madrid, , Spain

Hospital Virgen de la Victoria

Málaga, , Spain

Hospital Virgen de la Macarena

Seville, , Spain

Instituto Valenciano de Oncología (IVO)

Valencia, , Spain

Hospital Universitario Río Hortega

Valladolid, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Kantonsspital Baden

Baden, , Switzerland

Brustzentrum Basel Bethesda Spital

Basel, , Switzerland

Inselspital Bern

Bern, , Switzerland

Centre du Sein Fribourg

Fribourg, , Switzerland

Fondazione Oncologia Lago Maggiore

Locarno, , Switzerland

Kouros Moccia Oncologia

Locarno, , Switzerland

Luzerner Kantonsspital

Lucerne, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

BZ Bethanien

Zurich, , Switzerland

Brust-Zentrum AG Zürich

Zurich, , Switzerland

Countries

Austria; France; Hungary; Italy; Spain; Switzerland

References

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Other Identifiers

2018-003553-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BIG 18-02

Identifier Type: OTHER

Identifier Source: secondary_id

WI239003

Identifier Type: OTHER

Identifier Source: secondary_id

IBCSG 59-19

Identifier Type: -

Identifier Source: org_study_id