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

Breast Cancer Recurrent Clinical Trial

— POLAR  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03820830
• Other study ID #: IBCSG 59-19
• Secondary ID: 2018-003553-19BI
• Status: Recruiting
• Phase: Phase 3
• Start date: August 27, 2019
• Est. completion date: November 1, 2026

Study information

• Verified date: April 2024
• Source: ETOP IBCSG Partners Foundation
• Contact: Holly Shaw
• Phone: +17168340900
• Email: ibcsg59_polar[@]fstrf.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: November 1, 2026
• Est. primary completion date: July 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer Recurrent
• Breast Neoplasms
• Recurrence

Intervention

Drug:
• Palbociclib 125mg
Palbociclib 125 mg oral tablet taken daily for 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.

Locations

Country	Name	City	State
Austria	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
France	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
Hungary	National Institute of Oncology	Budapest
Italy	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
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 de La Coruña	La Coruna
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	HU Ramón y Cajal	Madrid
Spain	Hospital Virgen de la Victoria	Málaga
Spain	Hospital Universitario de Canarias	San Cristóbal de La Laguna	Tenerife
Spain	Hospital Virgen de la Macarena	Sevilla
Spain	Instituto Valenciano de Oncología (IVO)	Valencia
Spain	Hospital Universitario Río Hortega	Valladolid
Spain	Hospital Universitario Miguel Servet	Zaragoza
Switzerland	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	Luzern
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Brust-Zentrum AG Zürich	Zürich
Switzerland	BZ Bethanien	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation	Pfizer

Countries where clinical trial is conducted

Austria,  France,  Hungary,  Italy,  Spain,  Switzerland, 

References & Publications (9)

Aebi S, Gelber S, Anderson SJ, Lang I, Robidoux A, Martin M, Nortier JW, Paterson AH, Rimawi MF, Canada JM, Thurlimann B, Murray E, Mamounas EP, Geyer CE Jr, Price KN, Coates AS, Gelber RD, Rastogi P, Wolmark N, Wapnir IL; CALOR investigators. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol. 2014 Feb;15(2):156-63. doi: 10.1016/S1470-2045(13)70589-8. Epub 2014 Jan 16. — View Citation

Anderson SJ, Wapnir I, Dignam JJ, Fisher B, Mamounas EP, Jeong JH, Geyer CE Jr, Wickerham DL, Costantino JP, Wolmark N. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol. 2009 May 20;27(15):2466-73. doi: 10.1200/JCO.2008.19.8424. Epub 2009 Apr 6. — View Citation

Borner M, Bacchi M, Goldhirsch A, Greiner R, Harder F, Castiglione M, Jungi WF, Thurlimann B, Cavalli F, Obrecht JP, et al. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research. J Clin Oncol. 1994 Oct;12(10):2071-7. doi: 10.1200/JCO.1994.12.10.2071. — View Citation

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. — View Citation

Migliaccio I, Di Leo A, Malorni L. Cyclin-dependent kinase 4/6 inhibitors in breast cancer therapy. Curr Opin Oncol. 2014 Nov;26(6):568-75. doi: 10.1097/CCO.0000000000000129. — View Citation

Turner NC, Huang Bartlett C, Cristofanilli M. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Oct 22;373(17):1672-3. doi: 10.1056/NEJMc1510345. No abstract available. — View Citation

Wapnir IL, Aebi S, Geyer CE, Zahrieh D, Gelber RD, Anderson SJ, Robidoux A, Bernhard J, Maibach R, Castiglione-Gertsch M, Coates AS, Piccart MJ, Clemons MJ, Costantino JP, Wolmark N; IBCSG; BIG; NSABP. A randomized clinical trial of adjuvant chemotherapy for radically resected locoregional relapse of breast cancer: IBCSG 27-02, BIG 1-02, and NSABP B-37. Clin Breast Cancer. 2008 Jun;8(3):287-92. doi: 10.3816/CBC.2008.n.035. — View Citation

Wapnir IL, Price KN, Anderson SJ, Robidoux A, Martin M, Nortier JWR, Paterson AHG, Rimawi MF, Lang I, Baena-Canada JM, Thurlimann B, Mamounas EP, Geyer CE Jr, Gelber S, Coates AS, Gelber RD, Rastogi P, Regan MM, Wolmark N, Aebi S; International Breast Cancer Study Group; NRG Oncology, GEICAM Spanish Breast Cancer Group, BOOG Dutch Breast Cancer Trialists' Group; Breast International Group. Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol. 2018 Apr 10;36(11):1073-1079. doi: 10.1200/JCO.2017.76.5719. Epub 2018 Feb 14. — View Citation

Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, Arndt KT, Primeau T, Griffin E, Shao J, Crowder R, Lai JP, Norris JD, McDonnell DP, Li S. Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res. 2015 Nov 15;21(22):5121-5130. doi: 10.1158/1078-0432.CCR-15-0360. Epub 2015 May 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of invasive disease free survival of all randomized participants.	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.	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.
Secondary	Number of participants with treatment related adverse events.	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.	Adverse events will be collected from the date consent is signed, and during treatment until 30-60 days after treatment stops.
Secondary	Duration of breast cancer free interval of all randomized participants.	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.	Assessed from the date of randomization until the date of first documented breast cancer recurrence, or until approximately 4 years after treatment stops.
Secondary	Duration of distant recurrence free interval of all randomized participants.	Defined as the time from randomization until the date of first documented distant recurrence of breast cancer.	Assessed from the date of randomization until the date of first documented distant disease progression, or until approximately 4 years after treatment stops.
Secondary	Duration of overall survival of all randomized participants.	Defined as the time from randomization until death from any cause.	Assessed from the date of randomization until approximately 4 years after treatment stops, or until the date of death from any cause.