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Study of Efficacy of Ribociclib After Progression on CDK4/6 Inhibition in Patients With HR+ HER2- Advanced Breast Cancer (MAINTAIN)

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ClinicalTrials.gov Identifier: NCT02632045
Recruitment Status : Recruiting
First Posted : December 16, 2015
Last Update Posted : May 28, 2018
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Kevin Kalinsky, Columbia University

Brief Summary:
This is a randomized trial for patients with metastatic hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have progressed on an aromatase inhibitor plus a CDK4/6 inhibitor (either palbociclib or ribociclib) to either fulvestrant alone or fulvestrant with ribociclib (LEE-011). The purpose of the trial is to determine whether there is continued benefit for patients to remain on a CDK4/6 inhibitor at the time of switching anti-estrogen therapy. As ribociclib and palbociclib have a similar toxicity and drug profile and mechanism of action, we feel that it is appropriate for patients to receive either drug with an aromatase inhibitor prior to randomization.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Breast Carcinoma Drug: LEE-011 Drug: Fulvestrant Drug: Placebo Phase 2

Detailed Description:

Despite advances in early detection and therapeutic options, unresectable or metastatic breast cancer remains incurable and is one of the leading causes of cancer-related mortality. Breast cancer is a molecularly heterogeneous disease. This study will be evaluating estrogen receptor (ER) expression positivity and/or progesterone receptor (PgR) positivity of breast cancer with the absence of over-expression or amplification of HER2.

Inhibitors of the cyclin dependent kinases 4 and 6 (CDK4/6) have been developed and demonstrated impressive activity in patients with ER-positive HER2-negative breast cancer with marked improvements in progression free survival. This question is asking whether CDK 4/6 inhibition should be continued with hormone therapy in patients who will be switching their hormone therapy in the metastatic breast cancer setting.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : March 2016
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Ribociclib (LEE-011)/Fulvestrant
LEE-011 is administered orally, 600mg, daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks.
Drug: LEE-011
600 mg capsule (3x 200 mg capsules)
Other Name: ribociclib

Drug: Fulvestrant
500 mg injection
Other Name: Faslodex

Placebo Comparator: Placebo/Fulvestrant
Placebo is administered orally, 600mg daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks.
Drug: Fulvestrant
500 mg injection
Other Name: Faslodex

Drug: Placebo
600 mg capsule (3x 200 mg capsules)
Other Name: No other name




Primary Outcome Measures :
  1. Percent progression-free at 24 weeks [ Time Frame: Every 12 weeks, up to 24 weeks ]
    This study is designed to examine the proportion of patients who remain progression-free at 24 weeks from study entry (randomization day). Progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Disease status will be assessed with comprehensive radiographic studies every three treatment cycles (approximately every 12 weeks (+/- 1 week)).


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) in the fulvestrant/ribociclib group [ Time Frame: measured every 12 weeks, up to 6 months ]
    Evaluation of disease will be made according to RECIST criteria (version 1.1) in patients with measurable disease. As this study will enroll patients with measureable and un-measurable disease as defined by RECIST v1.1, ORR will only be assessed in evaluable patients. Response rates will be estimated as the proportion of enrolled patients who achieve complete or partial response rate.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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

Exclusion Criteria:

  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02632045


Contacts
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Contact: Dan Otap do2267@cumc.columbia.edu

Locations
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United States, Alabama
University of Alabama at Birmingham (UAB) Recruiting
Birmingham, Alabama, United States, 35294
Contact: Chris Vaklavas, MD    205-934-5677    cvaklavas@uabmc.edu   
Principal Investigator: Chris Vaklavas, MD         
United States, Illinois
Northwestern Medical Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Sarika Jain, MD    312-695-6180    cancertrials@northwestern.edu   
Principal Investigator: William Gradishar, MD         
United States, New York
Albert Einstein University / Montefiore Medical Center Recruiting
Bronx, New York, United States, 10461
Contact: Joseph Sparano, MD    718-405-8505    jsparano@montefiore.org   
Principal Investigator: Sun Young Oh, MD         
Northwell Health/Monter Cancer Center Recruiting
Lake Success, New York, United States, 11042
Contact: Mark Hoffman, MD    516-734-8869    MHoffma@northwell.edu   
Principal Investigator: Mark Hoffman, MD         
NYU Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Francisco Esteva, MD, PhD    212-731-5657    Francisco.Esteva@nyumc.org   
Principal Investigator: Francisco Esteva, MD, PhD         
Mount Sinai Medical Center Recruiting
New York, New York, United States, 10029
Contact: Amy Tiersten, MD    212-241-3300    amy.tiersten@mssm.edu   
Principal Investigator: Amy Tiersten, MD         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Kevin Kalinsky, MD, MS    212-305-1945    kk2693@cumc.columbia.edu   
Principal Investigator: Kevin Kalinsky, MD, MS         
Weill Cornell Medical Center Recruiting
New York, New York, United States, 10065
Contact: Marta Cobham, RN    212-821-0644    ela9082@med.cornell.edu   
Principal Investigator: Eleni Andreopoulou, MD         
Stony Brook Cancer Center Recruiting
Stony Brook, New York, United States, 11794
Contact: Lea Baer, MD    631-638-1000    Lea.Baer@stonybrookmedicine.edu   
Principal Investigator: Lea Baer, MD         
United States, Tennessee
Vanderbilt-Ingham Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Ingrid A Mayer, MD, MSC    800-811-8480    Ingrid.Mayer@vanderbilt.edu   
Principal Investigator: Ingrid A Mayer, MD         
United States, Wisconsin
University of Wisconsin School of Medicine Recruiting
Madison, Wisconsin, United States, 53792-001
Contact: Cancer Connect, MD    608-262-5223    cancerconnect@uwcarbone.wisc.edu   
Contact    800-622-8922      
Principal Investigator: Ruth O'Regan, MD         
Sponsors and Collaborators
Kevin Kalinsky
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Kevin Kalinsky, MD, MS Columbia University

Additional Information:
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Responsible Party: Kevin Kalinsky, Assistant Professor, Columbia University
ClinicalTrials.gov Identifier: NCT02632045     History of Changes
Other Study ID Numbers: AAAP9506
First Posted: December 16, 2015    Key Record Dates
Last Update Posted: May 28, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kevin Kalinsky, Columbia University:
Breast Neoplasms
Breast Cancer
Breast Carcinoma
Breast tumors
Cancer of the Breast

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs