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