Testing Whether Hormone Therapy With Ribociclib is as Effective as Chemotherapy Followed by Hormone Therapy With Ribociclib for the Treatment of High Anatomic Stage Breast Cancer With Low Recurrence Risk, The RxFINE-Low Trial
Purpose
This phase III trial compares standard of care hormone therapy plus ribociclib to chemotherapy followed by hormone therapy plus ribociclib for the treatment of patients with high anatomic stage breast cancer with low risk of the cancer returning (low risk recurrence). Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hormone therapy, with letrozole, anastrozole or exemestane, lowers the amount of estrogen made by the body. This may help stop the growth of tumor cells that need estrogen to grow. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Hormone therapy plus ribociclib may work as well as chemotherapy followed by hormone therapy plus ribociclib for the treatment of high anatomic stage breast cancer with low recurrence risk.
Conditions
- Anatomic Stage II Breast Cancer AJCC v8
- Anatomic Stage IIIA Breast Cancer AJCC v8
- Anatomic Stage IIIC Breast Cancer AJCC v8
- Estrogen Receptor-Positive Breast Carcinoma
- HER2-Negative Breast Carcinoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- STEP 0: Patient must be ≥ 18 years of age
- STEP 0: Patient must have an Eastern Cooperative Oncology Group (ECOG) performance
status of 0-2 within 28 days prior to Step 0 pre-registration
- STEP 0: Patient must be a postmenopausal woman or a man
- NOTE: Menopause can be determined by any of the following:
- Prior bilateral oophorectomy
- Age ≥ 60 years
- Age < 60 years with amenorrhea for ≥ 12 months and estradiol and follicle
stimulating hormone (FSH) levels in the postmenopausal range
- NOTE: FSH and estradiol levels should be repeated as clinically indicated to
ensure menopausal status in patients with breast cancer with
chemotherapy-induced amenorrhea
- STEP 0: Patient must meet one of the following staging criteria postoperatively
according to American Joint Committee on Cancer (AJCC) 8th edition criteria
- pT0-T3 with 3 positive ipsilateral lymph nodes (micro-or macrometastatic
disease) and no planned axillary lymph node dissection after definitive surgery
in the breast and axilla with curative intent.
- pT0-T3 with N2 or N3
- pT3 with N0-N3
- NOTES:
- Patients with T4 breast cancer are not eligible.
- Positive isolated tumor cells (ITCs) in axillary nodes without micro-
or macrometastasis are considered N0 for eligibility purposes.
- ITC does not contribute to nodal count for staging purposes
- STEP 0: Patient must have a primary breast tumor that is estrogen receptor (ER)
positive with > 10% ER expression by immunohistochemistry (IHC) as per 2020 American
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Estrogen
Receptor Testing Guideline.
- NOTE: ER 1-10% are reported as ER low positive. These tumors have less
endocrine-sensitive disease and are not eligible)
- STEP 0: Patient must have a primary breast tumor that is HER2-negative by current
ASCO/CAP guidelines utilizing immunohistochemistry and/or fluorescence in situ
hybridization (FISH)
- STEP 0: Patient may have multicentric or multifocal breast cancer if the highest
stage tumor meets eligibility criteria outlined above, and the tumor sites are felt
to represent a single disease process by local pathology or other sites of disease
are also ER-positive (> 10%) and HER2 negative, if such testing is completed. If
local pathology feels that multicentric or multifocal disease may represent distinct
disease processes repeat disease receptor testing is required other sites of disease
must also be also ER-positive (> 10%) and HER2-negative
- STEP 0: For patients who have undergone a lumpectomy, the margins of the resected
specimen or re-excision must be histologically free of invasive tumor and ductal
carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic
examination demonstrates tumor at the line of resection, additional excisions may be
performed to obtain clear margins. Positive posterior margin is allowed if surgeon
deems no further resection possible. Patients with margins positive for lobular
carcinoma in situ (LCIS) are eligible without additional resection
- STEP 0: For patients who have undergone mastectomy, the margins must be free of
residual gross tumor. Patients with microscopic positive margins are eligible if
post-mastectomy radiation treatment (RT) of the chest wall will be administered
- STEP 0: Patient must have undergone axillary staging with sentinel lymph node biopsy
(SLNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND)
- STEP 0: Patient must have no evidence of locoregional or distant metastatic disease
by clinical history and physical exam. Treating physician can consider additional
imaging evaluation per National Comprehensive Cancer Network (NCCN) guidelines
and/or institutional practice
- STEP 0: Patient must be able to have Oncotype DX testing performed.
- If Oncotype DX testing was previously performed, the results of Recurrence
Score (RS) must be available and must meet Step 1 eligibility criteria.
- If Oncotype DX testing was not performed yet, tissue from the core, excisional
biopsy or surgical specimen of the tumor lesion must be available and must be
shipped to Exact Sciences for determination of the Oncotype DX Recurrence Score
(RS) for eligibility and stratification.
- NOTE: Exact Sciences will notify the submitting institution of Recurrence
Score results within two (2) weeks of receipt of the tumor specimen.
Institutions will receive an email notification of eligibility status once
Recurrence Score results are entered into Rave by the submitting
institution
- STEP 0: Patient must have had their final cancer surgery for breast cancer
(including re-excision of margins) less than 16 weeks prior to Step 0
Pre-Registration.
- NOTE: This excludes additional surgery for reconstructive purposes
- STEP 0: Patients with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial
- STEP 0: Patients with synchronous DCIS or LCIS are eligible
- STEP 0: Patient with prior history of ER-negative DCIS diagnosed at least 5 years
prior to Step 0 Pre-Registration without evidence of recurrence are eligible
- STEP 0: Patient must not have a prior history of invasive ER-positive breast cancer.
Patients with a history of ER-negative breast cancer are eligible if they were
diagnosed at least 5 years prior to Step 0 Pre-Registration and have had no evidence
of recurrence
- STEP 0: Patients must not have received prior endocrine therapy such as tamoxifen,
raloxifene, or aromatase inhibitors for chemoprevention within 5 years prior to Step
0 Pre-Registration with the exception of a short course of endocrine therapy of less
than 6 weeks duration prior to Step 0 Pre-Registration.
- NOTE: The Oncotype Dx for study eligibility must be performed on specimen
obtained prior to initiation of any endocrine therapy
- STEP 0: Patient must not be concurrently using systemic hormone replacement therapy
(HRT). If receiving HRT at the time of breast cancer diagnosis, this must be
discontinued prior to Step 0 Pre-Registration with appropriate washout
- STEP 0: Absolute neutrophil count (ANC) ≥ 1,500/µL (obtained ≤ 28 days prior to Step
0 Pre-Registration)
- STEP 0: Hemoglobin ≥ 9.0 g/dL (obtained ≤ 28 days prior to Step 0 Pre-Registration)
- STEP 0: Platelets ≥ 100,000/µL (obtained ≤ 28 days prior to Step 0 Pre-Registration)
- STEP 0: Total bilirubin ≤ institutional upper limit of normal (ULN) or < 1.5 x ULN
for patients who have a bilirubin elevation in patients with well documented
Gilbert's disease or similar syndrome involving slow conjugation of bilirubin
(obtained ≤ 28 days prior to Step 0 Pre-Registration)
- STEP 0: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase
[SGPT]) ≤ 2.5 × institutional ULN (obtained ≤ 28 days prior to Step 0
Pre-Registration)
- STEP 0: Estimated glomerular filtration rate (eGFR) ≥ 30 mL/minute/1.73 m^2
(obtained ≤ 28 days prior to Step 0 Pre-Registration)
- STEP 0: Human immunodeficiency virus (HIV)-infected patients on effective
anti-retroviral therapy with undetectable viral load within 6 months of Step 0
Pre-Registration are eligible for this trial
- STEP 0: For patients with evidence of chronic hepatitis B virus (HBV) infection, the
HBV viral load must be undetectable on suppressive therapy, if indicated
- STEP 0: Patients with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For patients with HCV infection who are currently on treatment,
they are eligible if they have an undetectable HCV viral load
- STEP 0: Patients with known history or current symptoms of cardiac disease, or
history of treatment with cardiotoxic agents, should have a clinical risk assessment
of cardiac function using the New York Heart Association Functional Classification.
To be eligible for this trial, patients should be class 2 or better
- STEP 0: Patient must have a standard 12-lead electrocardiogram (ECG) within 28 days
prior to Step 0 Pre-Registration, documenting:
- QT interval using Fridericia's correction (QTcF) < 450 msec.
- Resting heart rate 50-90 beats per minute (determined from the ECG)
- STEP 0: Patient must have the ability to understand and the willingness to sign a
written informed consent document. Patients with impaired decision-making capacity
(IDMC) who have a legally authorized representative (LAR) or caregiver and/or family
member available will also be considered eligible
- STEP 0: Patient must not have comorbidities considered a safety risk for standard
adjuvant chemotherapy, endocrine therapy or CDK4/6 inhibitor as per Investigator's
discretion
- STEP 0: Patient must not have a contraindication to adjuvant chemotherapy based on
treating physician's discretion
- STEP 0: Patient must not have received prior chemotherapy for this malignancy
- STEP 0: Patient must not have received prior CDK4/6 inhibitor
- STEP 0: Patient must not have a known contraindication to ribociclib per current
Food and Drug Administration (FDA) indication
- STEP 0: Patient must not have a known hypersensitivity to any of the excipients of
ribociclib and/or endocrine therapy (ET) (e.g. rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy
allergy)
- STEP 0: Males must not expect to father children and males and their partners must
be willing to use highly effective methods of contraception while on protocol
treatment. Males must not donate sperm while on protocol treatment and for at least
12 weeks following the last dose of protocol treatment.
Highly effective methods include the following:
- Intrauterine device
- Bilateral tubal occlusion
- Vasectomized partner
- Sexual abstinence If the highly effective contraceptive methods are contraindicated
or strictly declined by the patient, or in the event of sexual activity of low
frequency, a combination of male condom with cap, diaphragm, or sponge with
spermicide (double-barrier methods) is also considered an acceptable birth control
method. Local regulation/guidelines are to be followed with regard to highly
effective birth control method, if more restrictive
- STEP 1: Patient must meet all Step 0 Pre-Registration eligibility criteria at
the time of their Step 1 randomization
- STEP 1: Patient must not have had any major surgery or radiotherapy within 14
days prior to Step 1 randomization
- STEP 1: Patient must have a Recurrence Score (RS) of 0-25 from Oncotype DX
testing from diagnostic biopsy or surgical specimen as reported by the Exact
Sciences assay
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm A (chemotherapy, hormone therapy, ribociclib) |
Patients receive their physician's choice of standard of care chemotherapy. Patients then receive their physician's choice of standard of care hormone therapy with letrozole, anastrozole, or exemestane PO QD on days 1-28 of each cycle, as well as ribociclib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days for at least 60 months for hormone therapy and up to 3 years for ribociclib, in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, bone scan, or FDG PET-CT scan and may optionally undergo blood sample collection throughout the study. |
|
|
Experimental Arm B (hormone therapy, ribociclib) |
Patients receive their physician's choice of standard of care hormone therapy with letrozole, anastrozole, or exemestane PO QD on days 1-28 of each cycle and ribociclib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days for at least 60 months for hormone therapy and up to 3 years for ribociclib, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, bone scan, or FDG PET-CT scan and may optionally undergo blood sample collection throughout the study. |
|
Recruiting Locations
Stamford, Connecticut 06904
Site Public Contact
203-323-8944
Bloomington, Illinois 61704
Canton, Illinois 61520
Carterville, Illinois 62918
Carthage, Illinois 62321
Decatur, Illinois 62526
Decatur, Illinois 62526
Eureka, Illinois 61530
Galesburg, Illinois 61401
Kewanee, Illinois 61443
Macomb, Illinois 61455
O'Fallon, Illinois 62269
O'Fallon, Illinois 62269
Ottawa, Illinois 61350
Pekin, Illinois 61554
Peoria, Illinois 61615
Peru, Illinois 61354
Princeton, Illinois 61356
Springfield, Illinois 62702
Site Public Contact
217-545-7929
Springfield, Illinois 62702
Site Public Contact
800-444-7541
Springfield, Illinois 62781
Washington, Illinois 61571
Bozeman, Montana 59715
Missoula, Montana 59804
West Columbia, South Carolina 29169
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed Description
PRIMARY OBJECTIVE: I. To determine whether optimal adjuvant endocrine therapy with CDK4/6 inhibitor is non-inferior to adjuvant chemotherapy followed by optimal endocrine therapy with CDK4/6 inhibitor as evaluated by invasive breast cancer-free survival (iBCFS). SECONDARY OBJECTIVES: I. To compare 5-year invasive disease-free survival (iDFS), distant disease-free survival (DDFS), distant recurrence-free survival (DRFS), recurrence-free interval (RFI), overall survival (OS), and breast cancer-specific survival (BCSS) in patients who receive adjuvant chemotherapy versus patients who do not. II. To compare the short-term and long-term toxicity profiles of each arm. EXPLORATORY OBJECTIVE: I. To create a biorepository of tumor tissue and peripheral blood biospecimens for future research. OUTLINE: STEP 0: Patients undergo Oncotype DX risk recurrence testing. Patients with an Oncotype DX recurrence score of 0-25 proceed to step 1. Patients with a recurrence score of 26-100 do not continue on the study. STEP 1: Patients are randomized to 1 of 2 arms. ARM A: Patients receive their physician's choice of standard of care chemotherapy. Patients then receive their physician's choice of standard of care hormone therapy with letrozole, anastrozole, or exemestane orally (PO) once daily (QD) on days 1-28 of each cycle, as well as ribociclib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days for at least 60 months for hormone therapy and up to 3 years for ribociclib, in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scan, bone scan, or fludeoxyglucose (FDG) positron emission tomography (PET)-CT scan and may optionally undergo blood sample collection throughout the study. ARM B: Patients receive their physician's choice of standard of care hormone therapy with letrozole, anastrozole, or exemestane PO QD on days 1-28 of each cycle and ribociclib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days for at least 60 months for hormone therapy and up to 3 years for ribociclib, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, bone scan, or FDG PET-CT scan and may optionally undergo blood sample collection throughout the study. Patients are followed every 3 months for 12 months from randomization, every 6 months for years 1-5 from randomization, then every 12 months for years 5-10 from randomization.