Clinical Trials /

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

NCT03820830

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: IBCSG 59-19
  • SECONDARY ID: 2018-003553-19
  • SECONDARY ID: BIG 18-02
  • SECONDARY ID: WI239003
  • NCT ID: NCT03820830

Conditions

  • Breast Cancer Recurrent

Interventions

DrugSynonymsArms
Palbociclib 125mgIbrance, PD-0332991Palbociclib plus standard endocrine therapy
Standard endocrine therapyPalbociclib plus standard endocrine therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Palbociclib plus standard endocrine therapyExperimentalPalbociclib 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.
  • Palbociclib 125mg
  • Standard endocrine therapy
Standard endocrine therapyActive ComparatorAromatase 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

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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

Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description:Defined as the time from randomization until the date of first documented distant recurrence of breast cancer.
Measure: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.
Safety Issue:
Description:Defined as the time from randomization until death from any cause.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:International Breast Cancer Study Group

Trial Keywords

  • hormone receptor positive breast cancer
  • HER2 receptor negative
  • CDK4/6 inhibitor

Last Updated