Clinical Trials /

Phase III Study of Palbociclib (PD-0332991) in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Aromatase Inhibitors

NCT02028507

Description:

This is an international (4 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to endocrine therapy (cohort 1: exemestane 25 mg daily, cohort 2: fulvestrant 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2 MBC are eligible if resistant to previous NSAI (letrozole or anastrozole) in cohort 1 or pevious AI (letrozole, anastrozole or exemestane) in cohort 2 defined as: recurrence while on or within 12 months after the end of adjuvant treatment with NSAI/AI or progression while on or within 1 month after the end of treatment with NSAI/AI for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Phase III Study of Palbociclib (PD-0332991) in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Aromatase Inhibitors
  • Official Title: Phase III Study of Palbociclib (PD-0332991) in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Aromatase Inhibitors

Clinical Trial IDs

  • ORG STUDY ID: GEICAM/2013-02
  • SECONDARY ID: 2013-003170-27
  • NCT ID: NCT02028507

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
PalbociclibPalbociclib plus Exemestane or Fulvestrant
CapecitabineCapecitabine
ExemestanePalbociclib plus Exemestane or Fulvestrant
FulvestrantPalbociclib plus Exemestane or Fulvestrant

Purpose

This is an international (4 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to endocrine therapy (cohort 1: exemestane 25 mg daily, cohort 2: fulvestrant 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2 MBC are eligible if resistant to previous NSAI (letrozole or anastrozole) in cohort 1 or pevious AI (letrozole, anastrozole or exemestane) in cohort 2 defined as: recurrence while on or within 12 months after the end of adjuvant treatment with NSAI/AI or progression while on or within 1 month after the end of treatment with NSAI/AI for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease.

Detailed Description

      296 patients have been randomized 1:1 between the experimental arm (Arm A: approximately 125
      patients treated with palbociclib plus exemestane) and the control arm (Arm B: approximately
      125 patients treated with capecitabine) before the approval of this protocol version (Cohort
      1).

      Approximately 300 patients will be randomized 1:1 between the experimental arm (Arm A:
      approximately 150 patients treated with palbociclib plus fulvestrant) and the control arm
      (Arm B: approximately 150 patients treated with capecitabine) from the approval of this
      protocol version (Cohort 2).
    

Trial Arms

NameTypeDescriptionInterventions
Palbociclib plus Exemestane or FulvestrantExperimentalPalbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Cohort 1: Exemestane 25 mg orally once daily. Cohort 2: Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.
  • Palbociclib
  • Exemestane
  • Fulvestrant
CapecitabineActive ComparatorCapecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.
  • Capecitabine

Eligibility Criteria

        Inclusion Criteria:

          1. The patient has signed the informed consent document.

          2. a) Patients in cohort 1: Females with histologically confirmed MBC whose disease is
             resistant to previous non-steroidal aromatase inhibitors (letrozole or anastrozole) b)
             Patients in cohort 2: Females with histologically confirmed MBC whosedisease was
             resistant to previous aromatase inhibitors (exemestane, letrozole or anastrozole).

             Resistance is defined as: Recurrence while on or within 12 months after the end of
             adjuvant treatment with NSAI/AI or Progression while on or within 1 month after the
             end of treatment with NSAI/AI for advanced disease.

          3. Previous chemotherapy is permitted either in the (neo) adjuvant setting and/or first
             line therapy for MBC (chemotherapy administered as "second adjuvant therapy" for
             locoregional recurrence should be considered as first line chemotherapy for MBC).

          4. It is not mandatory to have exemestane, letrozole or anastrozole as the most recent
             treatment before randomization but recurrence or progression of breast cancer while
             receiving (or immediatly after the enf of) the most recent systemic therapy has to be
             documented before randomization.

          5. Hormonal receptor positive (HR+) breast cancer based on local laboratory
             determination. HR+ defined as major or equal to 1 percent positive cells by IHC for ER
             and/or PgR.

          6. Documented HER2 negative breast cancer based on local laboratory determination on most
             recent tumor biopsy. HER2 negative tumor is determined as IHC score 0 or 1+ or
             negative by ISH (FISH/CISH/SISH) defined as a HER2/CEP17 ratio minor to 2 or for
             single probe assessment a HER2 copy number minor to 4.

          7. Measurable disease or at least one bone lesion, lytic or mixed (lytic+blastic), which
             has not been previously irradiated and is assessable by CT/MRI in the absence of
             measurable disease according to RECIST 1.1 criteria.

          8. Patient is at least 18 years of age.

          9. Eastern Cooperative Oncology Group (ECOG) Performance Status minor or equal to 1.

         10. Life expectancy major or equal to 12 weeks.

         11. Adequate organ and bone marrow function.

         12. Postmenopausal women defined as women with:

             Prior bilateral surgical oophorectomy, or Age > 60 years, or Age < 60 years and
             medically confirmed post-menopausal status defined as spontaneous cessation of regular
             menses for at least 12 consecutive months with no alternative pathological or
             physiological cause or follicle-stimulating hormone (FSH) and estradiol blood levels
             in their respective postmenopausal ranges

         13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical
             procedures to NCI CTCAE version 4.0 Grade minor or equal to 1 (except alopecia or
             other toxicities not considered a safety risk for the patient at investigator´s
             discretion).

         14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests and other study procedures.

        Exclusion Criteria:

          1. Have received more than 1 prior chemotherapy regimen for MBC. (NOTE: Chemotherapy
             administered as "second adjuvant therapy" for locoregional recurrence should be
             considered one prior chemotherapy for MBC).Other previous anticancer endocrine
             treatments for advanced disease are allowed.

          2. Patients with advanced, symptomatic, visceral spread that are at risk of
             life-threatening complications in the short term (including patients with massive
             uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis and
             over 50% liver involvement).

          3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or
             leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or
             progressive growth. Patients with a history of CNS metastases or cord compression are
             eligible if they have been definitively treated with local therapy (eg, radiotherapy,)
             and are clinically stable off anticonvulsants and steroids for at least 4 weeks before
             randomization.

          4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor (any agent whose mechanism of
             action is to inhibit the PI3 kinase-mTOR pathway) or capecitabine.

          5. a) Patients included in cohort 1: Prior treatment with exemestane in the metastatic
             setting. If the patient has received exemestane in the adjuvant setting and developed
             MBC, she will be eligible for the study provided:

               -  She has received letrozole/anastrozole as first-line MBC and progressed.

               -  At least 1 year has elapsed since the end of adjuvant exemestane treatment. b)
                  Patients included in Cohort 2: Prior treatment with fulvestrant in the metastatic
                  setting. If the patient has received fulvestrant in the adjuvant setting and
                  developed MBC, she will be eligible for the study provided:

               -  She has received letrozole/anastrozole as first-line MBC and progressed.

               -  At least 1 year has elapsed since the end of adjuvant fulvestrant treatment.

          6. Patients treated within the last 7 days prior to randomization with:

               -  Food or drugs that are known to be CYP3A4 inhibitors

               -  Drugs that are known to be CYP3A4 inducers

               -  Drugs that are known to prolong the QT interval

          7. Patients who received before randomization:

               -  Any investigational agent within 4 weeks

               -  Chemotherapy within a period of time that is minor than the cycle length used for
                  that treatment (e.g. less 3 weeks for fluorouracil, doxorubicine, epirubicine or
                  less than 1 week for weekly chemotherapy)

               -  Previous endocrine therapy is permitted without any window

               -  Radiotherapy within 2 weeks (all acute toxic effects must be resolved to NCI
                  CTCAE version 4.0 grade minor 1, except toxicities not considered a safety risk
                  for the patient at investigator´s discretion) but patients who received prior
                  radiotherapy to less than 25 per cent of bone marrow are not eligible independent
                  of when it was received

               -  Major surgery or other anti-cancer therapy not previously specified within 4
                  weeks, (all acute toxic effects must be resolved to NCI CTCAE version 4.0 grade
                  minor 1, except toxicities not considered a safety risk for the patient at
                  investigator´s discretion)

          8. Diagnosis of any other malignancy within 3 years prior to randomization, except for
             adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of
             the cervix.

          9. QTc major 480msec, family or personal history of long or short QT syndrome, Brugada
             syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).

         10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging
             drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).

         11. Any of the following within 6 months of randomization: myocardial infarction,
             severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade
             major or equal to 2, atrial fibrillation of any grade, coronary/peripheral artery
             bypass graft, symptomatic congestive heart failure, cerebrovascular accident including
             transient ischemic attack, or symptomatic pulmonary embolism.

         12. Difficulties to swallow tablets, malabsorption syndrome disease significantly
             affecting gastrointestinal function, resection of the stomach or small bowel, or
             active inflammatory bowel disease or chronic diarrhea.

         13. Known hypersensitivity to exemestane, palbociclib, capecitabine, fulvestrant or any of
             their excipients.

         14. Any of the following contraindications for chemotherapy with capecitabine:

               -  Known deficiency or family history of deficiency of dihydropyrimidine
                  dehydrogenase.

               -  Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or
                  chemically related analogues, such as brivudine.

         15. Only for patients in Cohort 2 any of the following contraindications for treatment
             with fulvestrant:

             - Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting
             factor deficiency) or long-term anticoagulant therapy (other than antiplatelet therapy
             and low dose warfarin) provided that the International Normalised Ratio (INR) is less
             than 1.6.

         16. Known human immunodeficiency virus infection.

         17. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the investigator, would make the patient
             inappropriate for entry into this study.

         18. Recent or active suicidal ideation or behavior
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS) based on the investigator's assessment
Time Frame:Approximately Septiembre 2019
Safety Issue:
Description:2 co-primary objetives: To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine in prolonging Progression-Free Survival (PFS) regardless of the ESR1 mutational status. To demonstrate that palbociclib in combination with endocrine therapy (exemestane or fulvestrant) is superior to capecitabine in prolonging PFS with estrogen receptor (ESR1) mutational status as wild type at study entry.

Secondary Outcome Measures

Measure:Objective Response: Complete Response (CR) plus Partial Response (PR) divided by the number of patients randomized with measurable disease
Time Frame:Approximately September 2019
Safety Issue:
Description:
Measure:Clinical Benefit: CR plus PR plus stable disease lasting more than 24 weeks divided by all randomized patients (ITT population).
Time Frame:Approximately September 2019
Safety Issue:
Description:
Measure:Response Duration (RD) (RD)
Time Frame:Approximately September 2019
Safety Issue:
Description:
Measure:Overall Survival (OS).
Time Frame:Approximately July 2020
Safety Issue:
Description:
Measure:Safety
Time Frame:Day 1 of each cycle.
Safety Issue:
Description:Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Spanish Breast Cancer Research Group

Trial Keywords

  • Palbociclib
  • Capecitabine
  • Hormonal Receptor positive
  • HER2 negative
  • Metastatic Breast Cancer
  • Resistance to non-steroidal Aromatase inhibitors
  • Fulvestrant
  • Exemestane
  • Aromatase inhibitor

Last Updated

January 9, 2018