Clinical Trial VICCBRE15147
A randoMized phAse II trIal of fulvestraNt wiTh or without Ribociclib After progression on AntI-estrogeN therapy plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer (MAINTAIN Trial)
- Protocol No. VICCBRE15147
- Open Date: 01/20/2017
- Staging: Phase II
- Age Group: Adults
- Scope: National
- Objective: To evaluate the progression-free survival (PFS) of fulvestrant with or without ribociclib after progression on an aromatase inhibitor plus cyclin-dependent kinase 4/6 inhibitor in patients with hormone receptor positive (HR+), HER2- breast cancer.
- Disease Sites: Breast
- Therapies: Hormonal Therapy; Molecular Targeted Agents / Immunotherapy / Biologics
- Drugs: Blinded Drug; Fulvestrant; LEE011; Letrozole (Femara)
- Participating Institutions: Vanderbilt University
- National Clinical Trial ID: NCT02632045
- Secondary Protocol No: AAAP9506
|Ages Eligible for Study:||18 Years and older|
|Genders Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
1. Men or women at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the breast with unresectable or metastatic disease.
2. Most recent tumor biopsy or surgical resection specimen must be either estrogen-receptor (ER) positive, progesterone receptors (PgR) positive, or both, as defined by immunohistochemistry (IHC) ≥1% (as per the American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines).
3. HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+ (i.e. indeterminate), a negative in situ hybridization (Fluorescent in situ hybridization (FISH), Chromogenic in situ hybridization (CISH), or Silver-enhanced in situ hybridization (SISH)) test is required by local laboratory testing. (as per the ASCO-CAP guidelines).
4. Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as goserelin. Postmenopausal status is defined by any one of the following criteria:
• Prior bilateral oophorectomy.
• Age ≥60 years.
• Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range per local normal.
If the patient does not meet criteria for postmenopausal status but is receiving ovarian ablation therapy with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin, the patient is eligible for this study, provided that the GnRH agonist is started at least 2 weeks prior to cycle 1 day 1 (C1D1) of anti-estrogen therapy.
5. Have evidence of measurable or unmeasurable disease.
6. Eastern Cooperative Group (ECOG) performance status of 0 or 1.
7. Scenario 1: No prior cdk 4/6 inhibitor. If patient has not previously received letrozole, letrozole will be supplied by Novartis. If previously progressed on letrozole, another aromatase inhibitor that the patient has not previously received is allowed, per standard of care (anastrazole or exemestane, not supplied by study). Ribociclib will be supplied by Novartis. If patient has previously received letrozole, anastrazole, and exemestane, (s)he is not eligible. No prior fulvestrant allowed.
8. Scenario 2: the patient must have received an aromatase inhibitor plus palbociclib as standard of care or received a cyclin D-cyclin-dependent kinase (CDK)4/6 inhibitor (palbociclib or ribociclib) as part of a clinical trial, and demonstrated evidence of disease progression. If the patient was enrolled in a randomized clinical trial involving ribociclib or palbociclib, then it must be known after study discontinuation and unblinding that the patient received the investigational drug and not placebo. Documentation of progression and duration of response on aromatase inhibitor plus CDK 4/6 inhibitor should be provided whenever possible. No prior fulvestrant allowed.
9. Adequate baseline laboratory studies (hematologic and chemistry), including the following parameters:
• Absolute neutrophil count ≥ 1500 per microliter, Platelets ≥ 75,000 per microliter, Hemoglobin level ≥ 8.0 gm/dL on screening complete blood count
• Potassium, sodium, total calcium (corrected only in the case of hypoalbuminemia), magnesium, and phosphorus within normal limits of the local laboratory (screening values can be rechecked after electrolyte repletion and before the first dose of study medication, if necessary).
• Serum creatinine level ≤ 1.5 mg/dL or estimated glomerular filtration rate > 50 mL/min.
• In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × the upper limit of normal (ULN). If the patient has liver metastases, ALT and AST should be < 5 × ULN.
• Total bilirubin ≤ 1.5 x ULN. (In patients with well documented Gilbert's Syndrome, total bilirubin ≤ 3 × ULN with direct bilirubin within normal range.)
• international normalized ratio (INR) ≤ 1.5
10. a) Written informed consent and HIPAA authorization obtained from the subject/legal representative prior to performing any protocol-related procedures b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
11. Must be able to swallow ribociclib and oral aromatase inhibitor, such as letrozole
1. Prior selective estrogen receptor down-regulator use (SERD), including fulvestrant
2. Patient has a known hypersensitivity to any of the excipients of ribociclib, aromatase inhibitors (such as letrozole) or fulvestrant
3. Active central nervous system (CNS) disease. History of CNS metastases or cord compression is allowable if the patient has been clinically stable for at least 4 weeks since completion of definitive treatment and is off systemic steroids. In the case of brain metastases, the patient must have stable or improved imaging at least 4 weeks after completion of definitive treatment. If there is evidence of active leptomeningeal disease, the patient is ineligible.
4. Identified as having visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. Visceral crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of the disease.
5. Received more than 1 prior systemic chemotherapy in the unresectable or metastatic setting. If the patient received 1 prior systemic chemotherapy, the patient is eligible. To clarify, this prior line can be single agent or combination (example, carboplatin/gemcitabine given concurrently). Patients do not need to have demonstrated disease progression on chemotherapy to be eligible. Having received prior targeted therapies for breast cancer (such as everolimus or experimental agents) does not affect eligibility for this study, with the exception of patients who have received the investigational CDK4/6 inhibitor abemaciclib (LY2835219). If the patient has previously received abemaciclib, the patient is not eligible for this study.
6. Completion of major surgery or radiation within 14 days prior to starting investigational drug or has not recovered from major side effects.
7. Residual acute toxic effects of prior anti-cancer therapy that have not resolved to CTCAE v.4 Grade ≤1 (except alopecia or other grade II or above toxicities not considered a safety risk for the patient at investigator's discretion).
8. Presence of a concurrent malignancy or malignancy diagnosed within 5 years of randomization, with the exception of basal or squamous cell carcinoma, non-melanomatous skin cancer, curatively resected cervical cancer, localized prostate cancer treated with curative intent, and stage I colorectal cancer treated with curative resection,
9. Patient has 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).
10. Patient has a known history of HIV infection (testing not mandatory)
11. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following:
• History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
• Documented cardiomyopathy
• Patient has a known Left Ventricular Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
• Long QT syndrome or family history of long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesaemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medications(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug) iii. Inability to determine the QTc interval
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade Atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)
12. Corrected QT interval (QTc) > 480 msec on screening electrocardiogram. If QTc prolongation is felt to be related to electrolyte imbalance, an EKG can be repeated after correction of electrolytes.
13. The presence of any other concurrent severe and/or uncontrolled medical condition that would, in the investigator or treating physician's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol. This includes uncontrolled infections that could potentially be exacerbated by anti-neoplastic treatment, active untreated or uncontrolled fungal bacterial or viral infections, etc.
14. Currently receiving treatment, including medications and herbal preparations, with known strong inducers or inhibitors of cytochrome p450 enzymes CYP3A4/5 medications that have a narrow therapeutic window and are predominately metabolized through CYP3A4/5 or herbal preparations/medications, dietary supplements, which cannot be discontinued at least one week prior to receiving investigational drug. Anti-retrovirals, anti-microbials, and anti-arrhythmics are the most common medications that interact with these enzymes. Section 5: Pharmaceutical Information and Appendix B for more information and a list of drugs that should not be used concurrently with ribociclib. An additional reference can be the CT scholar tool designed for Novartis Oncology
15. Patients who are receiving any other investigational agents concurrently or have received investigational agents within 14 days or 5 half-lives of the compound or active metabolites, whichever is longer before the first dose of the study treatment.
16. Subject is pregnant or nursing. Serum or urine Beta-Human chorionic gonadotropin (HCG) must be checked in all pre- and peri-menopausal patients. (Fulvestrant is pregnancy category D and CDK4/6 inhibitors have demonstrated teratogenicity/fetotoxicity in animal studies.)
17. The effects of ribociclib on the developing human fetus are unknown. For this reason and because the effects of chemotherapy are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 weeks after completion of ribociclib administration.