Phase III Study of Palbociclib in Combination With Exemestane or Fulvestrant vs. Chemotherapy (Capecitabine) in Hormonal Receptor Positive/HER2 Negative Metastatic Breast Cancer Patients With Resistance to Aromatase Inhibitors
Overview
- Phase
- Phase 3
- Intervention
- Palbociclib
- Conditions
- Metastatic Breast Cancer
- Sponsor
- Spanish Breast Cancer Research Group
- Enrollment
- 693
- Locations
- 37
- Primary Endpoint
- Progression-Free Survival (PFS)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
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 nonsteroidal aromatase inhibitors (NSAI) (letrozole or anastrozole) in cohort 1 or previous aromatase inhibitors (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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •The patient has signed the informed consent document.
- •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 whose disease 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.
- •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).
- •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 immediately after the enf of) the most recent systemic therapy has to be documented before randomization.
- •Hormonal receptor positive (HR+) breast cancer based on local laboratory determination. HR+ defined as major or equal to 1 percent positive cells by Immunohistochemistry (IHC) for ER and/or Progesterone Receptor (PgR).
- •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/Chromogenic In Situ Hybridization (CISH)/SISH) defined as a HER2/CEP17 ratio minor to 2 or for single probe assessment a HER2 copy number minor to
- •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.
- •Patient is at least 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status minor or equal to
Exclusion Criteria
- •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.
- •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).
- •Known active uncontrolled or symptomatic central nervous system (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.
- •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.
- •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.
- •Patients treated within the last 7 days prior to randomization with:
Arms & Interventions
Cohort 1: Palbociclib plus Exemestane
- Cohort 1:Palbociclib 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 Exemestane 25 mg orally once daily.
Intervention: Palbociclib
Cohort 1: Palbociclib plus Exemestane
- Cohort 1:Palbociclib 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 Exemestane 25 mg orally once daily.
Intervention: Exemestane
Cohort 1:Capecitabine
Cohort 1: Capecitabine, 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.
Intervention: Capecitabine
Cohort 2: Palbociclib plus Fulvestrant
- Cohort 2: Palbociclib 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 Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.
Intervention: Palbociclib
Cohort 2: Palbociclib plus Fulvestrant
- Cohort 2: Palbociclib 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 Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.
Intervention: Fulvestrant
Cohort 2:Capecitabine
Cohort 2:Capecitabine, 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.
Intervention: Capecitabine
Outcomes
Primary Outcomes
Progression-Free Survival (PFS)
Time Frame: Through study treatment, and average of 8 months
The primary efficacy variable is PFS based on the investigator's assessment. PFS is defined as the time from randomization to the first documented progressive disease based on the investigator's assessment, using RECIST version 1.1, or death from any cause, whichever occurs first. Estrogen Receptor 1 (ESR1) mutational status will be determined in circulating free DNA (cDNA) obtained from. Disease assessments will be performed at baseline and every 8 weeks (± 7 days) from the start of treatment and every 12 weeks (±7 days) after 120 weeks of treatment baseline plasma samples and will be prospectively determined before the interims or final analyses. ESR1 mutational status will be blinded to the patients, investigators and study team.
Secondary Outcomes
- PFS Estrogen Receptor 1 (ESR1) Wild Type(From randomization date to date of first documentation of progression or death (an average of 8 months))
- Overall Survival (OS) ESR1 Wild Type(From randomization until death (up to approximately 34 months))
- Objective Response Rate (ORR) ESR1 Wild Type(Through study treatment, and average of 8 months)
- Clinical Benefit Rate (CBR) ESR1 Wild Type(Through study treatment, and average of 8 months)
- Response Duration (RD) ESR1 Wild Type(Through study treatment, and average of 8 months)
- The Number of Participants Who Experienced Adverse Events (AE)(Through study treatment, and average of 8 months)
- Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment. An average of 8 months, an average of 1 year, and an average of 2 years.)
- Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment. An average of 8 months, an average of 1 year, and an average of 2 years.)
- Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)
- Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale(Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.)