Clinical trial NCT03820830: Palbociclib for HR Positive / HER2-negative Isolated Locoregional Recurrence of Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer Recurrent
Keywords: hormone receptor positive breast cancer
HER2 receptor negative
CDK4/6 inhibitor
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: Pfizer
First posted: 2019-01-29
Enrollment: 405
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Duration of invasive disease free survival of all randomized participants.
timeFrame: 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 outcomes:
measure: Number of participants with treatment related adverse events.
timeFrame: Adverse events will be collected from the date consent is signed, and during treatment until 30-60 days after treatment stops.
measure: Duration of breast cancer free interval of all randomized participants.
timeFrame: Assessed from the date of randomization until the date of first documented breast cancer recurrence, or until approximately 4 years after treatment stops.
measure: Duration of distant recurrence free interval of all randomized participants.
timeFrame: Assessed from the date of randomization until the date of first documented distant disease progression, or until approximately 4 years after treatment stops.
measure: Duration of overall survival of all randomized participants.
timeFrame: Assessed from the date of randomization until approximately 4 years after treatment stops, or until the date of death from any cause.
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medizinische Universität Graz (MUG)
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck - Univ.-Klinik f. Frauenheilkunde
city: Salzburg
country: Austria
facility: Uniklinikum Salzburg
city: Vienna
country: Austria
facility: MUW - Universitätsklinik für Innere Medizin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bordeaux
country: France
facility: Institut Bergonie
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: Caen
country: France
facility: Centre Francois Baclesse
city: Cholet
country: France
facility: Cêntre Hospitaler de Cholet
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Lorient
country: France
facility: Groupe hospitalier de Bretagne Sud, Hôpital du Scorff
city: Lyon
country: France
facility: Centre Leon Berard
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Gustave Roussy
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Aviano
country: Italy
facility: Cro Irccs
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
city: Brindisi
country: Italy
facility: PO Antonio Perrino Brindisi
city: Meldola
country: Italy
facility: Istituto scientifico Romagnolo per lo studio e la cura
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Novara
country: Italy
facility: AOU Maggiore Della Carita, University of Eastern Piedmont
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma
city: Pavia
country: Italy
facility: Istituti Clinici Scientifici Maugeri
city: Prato
country: Italy
facility: Ospedale S. Stefano
city: Rimini
country: Italy
facility: U.O. Oncologia, Ospedale Infermi
city: San Cristóbal de La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: Tenerife
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebrón
city: Barcelona
country: Spain
facility: Instituto Catalan de Oncologia L´Hospitalet
city: Bilbao
country: Spain
facility: Hospital de Basurto
city: Girona
country: Spain
facility: Institut Català d´Oncología (ICO)
city: La Coruna
country: Spain
facility: Hospital Universitario de La Coruña
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: HU Ramón y Cajal
city: Málaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Virgen de la Macarena
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología (IVO)
city: Valladolid
country: Spain
facility: Hospital Universitario Río Hortega
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Brustzentrum Basel Bethesda Spital
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Fribourg
country: Switzerland
facility: Centre du Sein Fribourg
city: Locarno
country: Switzerland
facility: Fondazione Oncologia Lago Maggiore
city: Locarno
country: Switzerland
facility: Kouros Moccia Oncologia
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zürich
country: Switzerland
facility: BZ Bethanien
city: Zürich
country: Switzerland
facility: Brust-Zentrum AG Zürich
Study officials:
affiliation: European Institute of Oncology
name: Elisabetta Munzone, MD
role: STUDY_CHAIR
References:
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.
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.
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.
citation: 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.
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.
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.
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.
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.
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.