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

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 evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03820830
Recruitment Status : Recruiting
First Posted : January 29, 2019
Last Update Posted : September 5, 2019
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
International Breast Cancer Study Group

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.


Condition or disease Intervention/treatment Phase
Breast Cancer Recurrent Drug: Palbociclib 125mg Drug: Standard endocrine therapy Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Open-label, Multicenter, Randomized Trial of Adjuvant Palbociclib in Combination With Endocrine Therapy Versus Endocrine Therapy Alone for Patients With Hormone Receptor Positive / HER2-negative Resected Isolated Locoregional Recurrence of Breast Cancer
Actual Study Start Date : August 27, 2019
Estimated Primary Completion Date : May 1, 2024
Estimated Study Completion Date : November 1, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Palbociclib

Arm Intervention/treatment
Experimental: 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.
Drug: Palbociclib 125mg
Palbociclib 125 mg oral tablet taken daily for 3 years from randomization
Other Names:
  • Ibrance
  • PD-0332991

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.

Active Comparator: 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.
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.




Primary Outcome Measures :
  1. Duration of invasive disease free survival of all randomized participants. [ Time Frame: Assessed from the date treatment starts until the date of first documented invasive local, regional or distant recurrence, a second invasive cancer or death, or until approximately 4 years after treatment stops. ]
    Defined as the time from randomization until first appearance of invasive local, regional or distant recurrence (including invasive ipsilateral breast tumour recurrence), invasive contralateral breast cancer, a second (non-breast) invasive cancer, or death from any cause. The sites of first invasive disease events will be compared between treatment groups using a stratified log-rank test and will be tabulated.


Secondary Outcome Measures :
  1. Number of participants with treatment related adverse events. [ Time Frame: Adverse events will be collected from the date consent is signed, and during treatment until 30-60 days after treatment stops. ]
    Adverse events, defined as any untoward medical occurrence, will be collected using CTCAE v5. All grades for targeted adverse events will be collected and all grades ≥3 for non-targeted adverse events. The maximum grade of each targeted adverse event during the protocol treatment phase will be determined, the frequencies summarized and tabulated according to grade and treatment assignment.

  2. Duration of breast cancer free interval of all randomized participants. [ Time Frame: Assessed from the date of randomization until the date of first documented breast cancer recurrence, or until approximately 4 years after treatment stops. ]
    Defined as the time from randomization until the date of first documented appearance of invasive local, regional or distant recurrence (including ipsilateral tumour recurrence), or invasive contralateral breast cancer.

  3. Duration of distant recurrence free interval of all randomized participants. [ Time Frame: Assessed from the date of randomization until the date of first documented distant disease progression, or until approximately 4 years after treatment stops. ]
    Defined as the time from randomization until the date of first documented distant recurrence of breast cancer.

  4. Duration of overall survival of all randomized participants. [ Time Frame: Assessed from the date of randomization until approximately 4 years after treatment stops, or until the date of death from any cause. ]
    Defined as the time from randomization until death from any cause.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed invasive breast cancer, defined as first proven ipsilateral local and/or regional recurrence in the breast in at least one of these sites: breast; the chest wall including mastectomy scar and/or skin; axillary or internal mammary lymph nodes.
  • Completion of locoregional therapy: gross excision of recurrence within 6 months prior to randomization; radiotherapy (if given) more than 2 weeks prior to randomization
  • Negative or microscopically involved margins
  • Female or male aged 18 years or older
  • ECOG performance status 0 or 1
  • Recurrent tumor must be hormone receptor positive: ER+ and/or PgR+ ≥1% by IHC
  • 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
  • Normal hematological, renal, and liver function
  • The patient agrees to make tumor (diagnostic core biopsy or surgical specimen of ipsilateral isolated locoregional recurrence) available for submission for central pathology review
  • Patients must either be planned to initiate, or have already started, endocrine therapy for ipsilateral isolated locoregional recurrence
  • Written Informed Consent prior to randomization

Exclusion Criteria:

  • Recurrence of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules) not surgically removable
  • 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).
  • Bilateral invasive breast cancer (in situ carcinoma of the contralateral breast is allowed)
  • Inflammatory breast cancer
  • 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.
  • Previous treatment with palbociclib or any other CDK 4/6 inhibitors
  • 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)
  • 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
  • Contraindications or known hypersensitivity to the palbociclib or excipients
  • Pregnant or lactating women; lactation has to stop before randomization

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03820830


Contacts
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Contact: Holly Shaw +17168340900 ibcsg59_polar@fstrf.org
Contact: Adriana Karausch ibcsg59_polar@fstrf.org

Locations
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Hungary
National Institute of Oncology Not yet recruiting
Budapest, Hungary
Contact: Gábor Rubovszky, MD       garub@oncol.hu   
Medical University Not yet recruiting
Debrecen, Hungary
Contact: Arkosy Péter       arkosy.peter@med.unideb.hu   
Italy
Cro Irccs Not yet recruiting
Aviano, Italy
Contact: Simon Spazzapan, MD       spazzapan@cro.it   
ASST Papa Giovanni XXIII Not yet recruiting
Bergamo, Italy
Contact: Carlo Tondini, MD       carlo.tondini@asst-pg23.it   
PO Antonio Perrino Brindisi Not yet recruiting
Brindisi, Italy
Contact: Cinieri Saverio, MD       saverio.cinieri@ieo.it   
Istituto scientifico Romagnolo per lo studio e la cura Not yet recruiting
Meldola, Italy
Contact: Andrea Rocca, MD       andrea.rocca@irst.emr.it   
Istituto Europeo di Oncologia Not yet recruiting
Milan, Italy
Contact: Elisabetta Munzone, MD       elisabetta.munzone@ieo.it   
AOU Maggiore Della Carita, University of Eastern Piedmont Not yet recruiting
Novara, Italy
Contact: Alessandra Gennari, MD       alessandra.gennari@med.uniupo.it   
Istituti Clinici Scientifici Maugeri Not yet recruiting
Pavia, Italy
Contact: Antonio Bernardo, MD       antonio.bernardo@icsmaugeri.it   
Ospedale S. Stefano Not yet recruiting
Prato, Italy
Contact: Laura Biganzoli, MD       laura.biganzoli@uslcentro.toscana.it   
Switzerland
Kantonsspital Baden Recruiting
Baden, Switzerland
Contact: Cornelia Leo, MD       cornelia.leo@ksb.ch   
Brustzentrum Basel Bethesda Spital Not yet recruiting
Basel, Switzerland
Contact: David Thorn, MD       dr.david.thorn@hin.ch   
Inselspital Bern Not yet recruiting
Bern, Switzerland
Contact: Manuela Rabaglio, MD       manuela.rabaglio@insel.ch   
Centre du Sein Fribourg Not yet recruiting
Fribourg, Switzerland
Contact: Rosset, MD       Rossetl@hin.ch   
Luzerner Kantonsspital Recruiting
Luzern, Switzerland
Contact: Stefan Aebi, Prof.       stefan.aebi@luks.ch   
Kantonsspital Winterthur Recruiting
Winterthur, Switzerland
Contact: Andreas Muller, MD       andreas.mueller@ksw.ch   
Brust-Zentrum AG Zürich Recruiting
Zürich, Switzerland
Contact: Uwe Gueth, Prof.       u.gueth@brust-zentrum.ch   
UniversitätsSpital Zürich Not yet recruiting
Zürich, Switzerland
Contact: Konstantin Dedes, MD       konstantin.dedes@usz.ch   
Sponsors and Collaborators
International Breast Cancer Study Group
Pfizer
Investigators
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Study Chair: Elisabetta Munzone, MD European Institute of Oncology

Publications:

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Responsible Party: International Breast Cancer Study Group
ClinicalTrials.gov Identifier: NCT03820830     History of Changes
Other Study ID Numbers: IBCSG 59-19
2018-003553-19 ( EudraCT Number )
BIG 18-02 ( Other Identifier: Breast International Group (BIG) )
WI239003 ( Other Identifier: Pfizer number )
First Posted: January 29, 2019    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by International Breast Cancer Study Group:
hormone receptor positive breast cancer
HER2 receptor negative
CDK4/6 inhibitor
Additional relevant MeSH terms:
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Breast Neoplasms
Recurrence
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Disease Attributes
Pathologic Processes
Palbociclib
Hormones
Estrogen Receptor Modulators
Selective Estrogen Receptor Modulators
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Hormone Antagonists
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action