Ribociclib in Treating Patients with Estrogen Receptor Positive Breast Cancer
- Participants must have biopsy proven localized estrogen receptor (ER) positive (+) (>= 10%), HER2 negative, any grade, invasive breast cancer; pathological stage (including post-neoadjuvant therapy) with any T, any N or M0 by American Joint Committee on Cancer (AJCC) eighth (8th) edition staging (Part 1), and pathological stage IIB or III by AJCC 8th edition staging (Part 2); restaging radiological scans at baseline is as per discretion of treating physician; invasive breast cancer must be ER+ in >= 10% of the cells and HER2 negative (immunohistochemistry [IHC] 0 or 1+ and/or fluorescence in situ hybridization [FISH] negative with a ratio < 2) by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines; for IHC 2+, the tumor must be FISH negative with a ratio < 2; ER, progesterone receptor (PR) and HER2 measurements should be performed according to institutional (local) guidelines, in a Clinical Laboratory Improvement Act (CLIA)-approved setting; evaluation for metastatic disease is not required in the absence of symptoms; patients must have completed definitive surgery for breast cancer
- Confirmation of adequate archival tissue (15-20 unstained slides cut at 5 um or 1 block) required before study entry; if adequate tissue not available, principal investigator (PI) approval is required prior to study entry
- No prior history of other malignancies within past 5 years (besides breast cancer); individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin; no concurrent malignancy or other serious medical condition as deemed by the investigator
- Participants may or may not have received (neo)adjuvant chemotherapy, but must be at least 4 weeks after last dose of chemotherapy and/or biological therapy at the time of screening, with no more than grade 1 residual toxicity (except =< grade 2 neuropathy or =< grade 2 alopecia)
- Participants may or may not have received adjuvant radiotherapy, but must be at least 4 weeks after last dose radiotherapy at the time of screening, with no more than grade 1 residual toxicity
- Pre- and postmenopausal women are eligible; premenopausal women must have a negative serum or urine pregnancy test; pregnancy testing does not need to be pursued in female patients who are: * Age >= 60 years; OR * Age < 60 with intact uterus AND amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; OR * Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation
- Corrected QT (QTc) (Fridericia’s formula) < 470 ms
- No history of prior CDK 4/6 inhibitor use (except usage in window of opportunity study for fewer than 28 days) for Part 1; for Part 2, prior CDK 4/6 inhibitor is permitted provided it was more than 12 months ago (from consent date)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)
- Patients may enroll within 10 years of breast cancer diagnosis, as long as there is a plan for at least 1 more year of adjuvant endocrine therapy; for Part 2, patients must currently be on endocrine therapy in the adjuvant setting and must have received (neo)adjuvant endocrine therapy for at least 24 months (cumulative duration)
- Ability to understand and the willingness to sign a written informed consent document; patient must sign the informed consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements
- Participants may have been on adjuvant endocrine therapy, either tamoxifen or aromatase inhibitor (AI); prior use of any AI, including letrozole, anastrozole or exemestane, or tamoxifen is allowed; however, tamoxifen use is not allowed during the study with ribociclib; patients on tamoxifen interested in this trial could be switched to AI on cycle 1 day 1 (C1D1) (or before/during screening); concurrent gonadotrophin releasing hormone (GNRH) agonist is allowed, and is recommended with AI in pre/peri-menopausal patients
- Absolute neutrophil count >= 1.5 x 10^9/L (at screening)
- Platelets >= 100 x 10^9/L (at screening)
- Hemoglobin >= 9.0 g/dL (at screening)
- Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication; minor toxicities that are not clinically significant are allowed with overall approval by the PI (at screening); requirements regarding potassium, magnesium, and phosphorous will not be changed due to their relationship with QTcF
- Serum creatinine < 1.5 mg/dL OR creatinine clearance >= 50 mL/min (at screening)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x institutional upper limit of normal (ULN) (at screening)
- Total bilirubin < institutional ULN; or total bilirubin =< 3.0 x institutional ULN or direct bilirubin =< 1.5 x institutional ULN in patients with well- documented Gilbert’s syndrome (at screening)
- ADDITIONAL INCLUSION CRITERIA FOR PART 2
- ER+ (>= 10%), HER2 negative, any grade, invasive breast cancer, with pathological stage IIB or III (including post-neoadjuvant therapy)
- Currently on adjuvant endocrine therapy (tamoxifen and/or AI), and must have received (neo)adjuvant endocrine therapy for at least 24 months (cumulative duration)
- Detectable ctDNA in a CLIA-certified lab (separate pre-screening consent available) within the past six months
- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; there is no minimum washout for endocrine therapy
- Participants who are receiving any other anti-cancer investigational agents
- History of prior PI3K, mTOR inhibitor use for breast cancer (except usage in window of opportunity study for fewer than 28 days)
- Participants who previously enrolled to Part 1 of Dana-Farber/Harvard Cancer Center (DF/HCC) Protocol 17-232
- Participants with known brain metastases, or any other metastases from cancer
- Participants receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; herbal products supplements (such as cannabidiol [CBD] oil) can be considered on a case-by-case basis by Overall PI
- Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) are ineligible
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: * History of angina pectoris, symptomatic pericarditis, coronary artery bypass graft (CABG) or myocardial infarction within 6 months prior to study entry * Documented cardiomyopathy * History of cardiac failure, significant/symptomatic bradycardia, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or any of the following: ** Known risk to prolong the QT interval or induce torsade’s de pointes ** Uncorrected hypomagnesemia or hypokalemia ** Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg ** Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse ** On screening, inability to determine the corrected QT using Fridericia's formula (QTcF) interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 470 screening ECG (based on a mean of 3 ECGs)
- History of hypersensitivity to ribociclib or any of its components
- Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible; these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
- Pregnant women are excluded from this study because the safety of ribociclib is not established in pregnant women; for this reason and because CDK4/6 agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential (WOCBP) and men must agree to use adequate contraception prior to study entry, for the duration of treatment, and for at least 3 months after the completion of treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately; prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy; in addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential; all WOCBP must have a negative pregnancy test within 72 hours prior to receiving the first dose of the investigational agent(s); registration may occur prior to this pregnancy test; if the pregnancy test is positive, the patient must not receive protocol treatment and must not continue in the study; WOCBP is defined as follows: * Any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a bilateral oophorectomy) OR * Any female who is not postmenopausal (defined as amenorrhea >= 12 consecutive months, or women on hormone replacement therapy [HRT] with documented plasma follicle-stimulating hormone [FSH] level > 35 mIU/ml) * Even women who are using oral, implanted, or injectable contraceptive hormones or mechanical products (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), should be considered to be a WOCBP
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 12 weeks after study drug discontinuation; women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential; highly effective contraception methods include: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception * Use of luteinizing hormone-releasing hormone (LHRH) agonist with estrogen level in post-menopausal range and one form of barrier method contraception * In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment; Note: while oral contraceptives are allowed, they should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction
I. To evaluate the safety and tolerability of two schedules of adjuvant ribociclib (intermittent or continuous dosing) in combination with endocrine therapy for 12 cycles in patients with localized post-menopausal breast cancer. (Part 1)
II. To determine tumor circulating tumor deoxyribonucleic acid (ctDNA) response after 12 cycles of adjuvant ribociclib in combination with endocrine therapy vs endocrine therapy alone in patients with localized post-menopausal breast cancer and elevated ctDNA. (Part 2)
I. To compare the adverse effects, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) grading, in patients treated with endocrine therapy within 5 years versus those on endocrine therapy > 5 years.
II. To determine the percentage (%) of patients who have switch in endocrine therapy.
III. To determine the time to relapse and disease-free survival (DFS) among patients receiving endocrine therapy with the addition of ribociclib.
IV. To determine tumor ctDNA response after 3 cycles of adjuvant ribociclib in combination with endocrine therapy vs endocrine therapy (standard of care) in patients with elevated ctDNA.
V. To assess potential predictive biomarkers of response to endocrine therapy and ribociclib, particularly cyclin-D amplification. (Exploratory)
OUTLINE: Patients are assigned to 1 of 2 parts.
PART 1: This is a dose-escalation study. Patients are randomized to 1 of 2 arms.
ARM I (CONTINUOUS): Patients receive ribociclib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
ARM II (INTERMITTENT): Patients receive ribociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
PART 2: Patients are randomized to 1 of 2 arms.
ARM III: Patients receive ribociclib PO QD on days 1-28 and standard of care aromatase inhibitor. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
ARM IV: Patients receive standard of care aromatase inhibitor or tamoxifen. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6-12 months for up to 3 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
- Primary ID 17-232
- Secondary IDs NCI-2018-00166
- Clinicaltrials.gov ID NCT03285412