Details

Details

Title A randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for hormone receptor positive (HR+) / human epidermal growth factor receptor 2 (HER2)-negative early breast cancer

IRB AFT1116

CC 16-1148

Hospital Fairview, Hillcrest, Main Campus

Phase Phase 3

Disease Breast

Drug Palbociclib

Description

Description

Primary Objective
  • To compare invasive disease-free survival (iDFS) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC).
Secondary Objectives
  • To compare the following endpoints: iDFS excluding second primary cancers of non-breast origin, distant recurrence-free survival (DRFS), locoregional recurrences-free survival (LRRFS), and overall survival (OS).
  • To compare the safety of 2 years of palbociclib with adjuvant endocrine therapy versus adjuvant endocrine therapy alone.
Translational Science Principal Objective
  • To compare baseline tumor tissue to determine whether there is prognostic or predictive utility for defined genomic subtypes (luminal A, luminal B and non-luminal) with respect to iDFS and OS.
Translational Science Additional Objectives
  • To evaluate iDFS and OS in other genomically-defined breast cancer prognostic, theranostic, or predicted subgroups based on pre-specified genomic assays
  • To evaluate baseline tumor- and blood-based markers as predictors of benefit from the addition of palbociclib to endocrine therapy.
  • To evaluate tumor- and blood-based markers at time of disease recurrence for mechanisms of resistance to palbociclib and endocrine therapy.
  • To perform exploratory analyses of serum and plasma samples over time to investigate the predictive and prognostic value of novel biomarkers in this specific trial setting related to efficacy or safety of the agent.
  • To compare serial levels of circulating cell-free DNA (cfDNA) in patients receiving palbociclib and endocrine therapy versus endocrine therapy alone.
  • To evaluate pharmacogenomic and pharmacogenetic predictors of toxicity and efficacy of palbociclib and endocrine therapy and to endocrine therapy alone.
Clinical Science Objectives
  • To evaluate adherence to oral therapy in patients receiving palbociclib and endocrine therapy.
  • To determine the association of BMI with the efficacy of palbociclib and endocrine therapy.
Patient-Reported Outcomes Objectives
  • To compare patient-reported quality of life, fatigue, arthralgia, alopecia, menstrual function, and endocrine symptoms of HR+/HER2- breast cancer patients randomized to receive palbociclib plus adjuvant standard endocrine therapy versus standard endocrine therapy alone overall and by subgroups defined by age at randomization (≤50 and >50) and initial endocrine therapy (tamoxifen and AI) at multiple pre-specified time points.
Inclusion Criteria

Inclusion Criteria

Patient/Disease Specifics

  1. Signed informed consent obtained prior to any study specific assessments and procedures.
  2. Age ≥18 years (or per national guidelines).
  3. Premenopausal and postmenopausal women or men with Stage II (Stage IIA limited to a maximum of 1000 patients) or Stage III early invasive breast cancer per AJCC (American Joint Committee on Cancer) Breast Cancer Staging version 7 / UICC (Union for International Cancer Control). Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice (in patients where there may be a reasonable suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and symptoms). If performed, reports of these examinations must be available. Examination type for staging, i.e. X-ray, sonography, bone scan, CT, MRI, and/or PET-CT, is at the discretion of the investigator. If neoadjuvant systemic therapy was received (either chemotherapy or endocrine therapy), either initial clinical stage (determined by physical and/or radiologic examination) or post-operative pathologic stage can be used for eligibility purposes, with the higher stage determining eligibility.
  4. Patients with multicentric and/or multifocal and/or bilateral early invasive breast cancer whose histopathologically examined tumors all meet pathologic criteria for ER+ and/or PR+ and HER2-.
  5. Patients must have histologically confirmed hormone receptor positive (ER+ and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines. Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment. Testing may occur on diagnostic core or surgical tumor tissue.
  6. Patients must have undergone breast surgery for the current malignancy.
  7. A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be transmitted to a central sample repository and confirmation of receipt must be available prior to randomization. For details please refer to section 8.2.
  8. ECOG performance status 0-1.
  9. Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
  10. Serum or urine pregnancy test must be negative within 7 days of randomization, in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with palbociclib if they are in arm A. Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository).

    11. Prior Treatment Specifics

  11. Patients may or may not have received neo/adjuvant therapy, but must be after last dose of chemotherapy and/or biologic therapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
  12. Patients may or may not have received breast/axilla/ post-mastectomy chest wall radiotherapy, but must be after last dose of radiotherapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
  13. Patients must have sufficient resolution of any surgical side effects from the last surgery per physician assessment, with no active wound healing complications at the time of randomization.
  14. Patients must either be initiating or have already started adjuvant hormonal treatment. Patients may already have initiated endocrine therapy at the time of randomization, but randomization must take place within 12 months of date of histological diagnosis and within 6 months of initiating standard adjuvant endocrine therapy. Patients who received neoadjuvant endocrine therapy are eligible as long as they are enrolled within 12 months of initial histological diagnosis and after completing no more than 6 months of adjuvant endocrine therapy. Patients may be receiving either tamoxifen or aromatase inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal patients and men, concurrent LHRH agonist use is allowable and may also be ongoing at the time of randomization.

    15. Baseline Body Function Specifics

  15. Absolute neutrophil count ≥ 1,500/mm3.
  16. Platelets ≥ 100,000/mm3.
  17. Hemoglobin ≥ 10g/dL.
  18. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome.
  19. Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 x institutional ULN.
  20. Serum creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.

Exclusion Criteria

Exclusion Criteria

  1. Concurrent therapy with other Investigational Products.
  2. Prior therapy with any CDK inhibitor.
  3. Patients with Stage I or IV breast cancer are not eligible. Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice (in patients where there may be a reasonable suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and symptoms). If performed, reports of these examinations must be available. Examination type for staging, i.e. X-ray, sonography, bone scan, CT, MRI, and/or PET-CT, is at the discretion of the investigator.
  4. History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
  5. Patients receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization (see Section 9.5.2.1 for list of CYP3A inhibitors and inducers).
  6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
  7. Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
  8. Patients with a history of any malignancy are ineligible except for the following circumstances:
    • Patients with a malignancy history other than invasive breast cancer are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy.
    • Patients with the following cancers are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic non-melanomatous skin cancers.
  9. Patients are not eligible if they have previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy. This includes use for prophylactic reasons, including treatment of osteoporosis or cancer prevention with tamoxifen, raloxifene or AI. Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis.
  10. Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
  11. Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc.
  12. Patients receiving concurrent exogenous hormone therapy (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable.