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

NCT02632045 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: AAAP9506
• Study Type: interventional
• Target: 169
• Locations: 1 country
• Sites: 13

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, the investigators feel that it is appropriate for patients to receive either drug with an aromatase inhibitor prior to randomization.

Conditions

Metastatic Breast Cancer; Breast Carcinoma

Keywords

Breast Neoplasms; Breast Cancer; Breast Carcinoma; Breast tumors; Cancer of the Breast

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  Progression free survival (PFS) is defined as the interval from the time of randomization until objective disease progression (local assessment) or death from any cause. Disease status will be assessed with comprehensive radiographic studies every three treatment cycles (approximately every 12 weeks (+/- 1 week)). Disease progression as assed by RECIST 1.1 defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

  Up to approximately 30 months

Secondary Outcomes (2)

• Overall Response Rate (ORR)

  measured every 12 weeks, up to 6 months

• Clinical Benefit Rate (CBR)

  Up to 24 weeks

Study Arms (2)

Ribociclib (LEE-011)/Fulvestrant

EXPERIMENTAL

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; Drug: Fulvestrant

Placebo/Fulvestrant

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

LEE-011 DRUG

600 mg capsule (3x 200 mg capsules)

Also known as: ribociclib

Ribociclib (LEE-011)/Fulvestrant

Fulvestrant DRUG

500 mg injection

Also known as: Faslodex

Placebo/Fulvestrant; Ribociclib (LEE-011)/Fulvestrant

Placebo DRUG

600 mg capsule (3x 200 mg capsules)

Also known as: No other name

Placebo/Fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men or women at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the breast with unresectable or metastatic disease.
• 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).
• 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).
• 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, toremifen, 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 C1D1 of anti-estrogen therapy.
• Have evidence of measurable or unmeasurable disease.
• Eastern Cooperative Group (ECOG) performance status of 0 or 1.
• No prior cdk 4/6 inhibitor (Closed to Accrual). 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. For scenario 1, patients are allowed to have started the aromatase inhibitor within 4 consecutive weeks prior to protocol registration. For instance, it is acceptable for patient who will be treated with letrozole in scenario #1, to have started letrozole within 4 consecutive weeks prior to protocol registration. No prior fulvestrant allowed.
• Scenario 2: the patient must have received an aromatase inhibitor (letrozole, arimidex, exemestane) or tamoxifen or fulvestrant plus palbociclib as standard of care or received a CDK4/6 inhibitor (palbociclib or ribociclib or abemaciclib), and demonstrated evidence of disease progression. If the patient was enrolled in a randomized clinical trial involving ribociclib or abemaciclib or palbociclib (such as the MONALEESA or PALOMA series of trials), then it must be known after study discontinuation and unblinding that the patient received the investigational drug and not placebo. Ribociclib or abemaciclib or palbociclib can also be given as standard of care. Documentation of progression and duration of response on aromatase inhibitor or tamoxifen plus CDK 4/6 inhibitor should be provided whenever possible. If patient received prior fulvestrant, exemestane must be the hormone therapy backbone in the randomization. If patient received prior exemestane, fulvestrant must be the hormone therapy backbone in the randomization. If neither has been administered, selection of fulvestrant or exemestane in the randomization will be per investigator discretion.
• 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.

You may not qualify if:

• Patient has a known hypersensitivity to any of the excipients of ribociclib, aromatase inhibitors (such as letrozole) or fulvestrant
• 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.
• 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.
• 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. Having received prior therapies for breast cancer (such as everolimus or experimental agents) does not affect eligibility for this study.
• Completion of major surgery, chemotherapy, targeted therapy (such as everolimus or experimental agents\_ or radiation within 14 days prior to starting investigational drug or has not recovered from major side effects. There is no required washout period from completion of prior anti-estrogen therapy (either scenario) or prior CDK 4/6 inhibitor (if scenario 2) to initiation of ribociclib/placebo and anti-estrogen on trial.
• Residual acute toxic effects of prior anti-cancer therapy that have not resolved to CTCAE v.4 Grade ≤1. Exception to this criterion: patients with grade 1 taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk for the patient as per investigator's discretion, are allowed to enter the study.
• 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.
• 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).
• Patient has a known history of HIV infection (testing not mandatory).
• 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 hypocalcemia, 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

Sponsors & Collaborators

• Melissa K Accordino: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (13)

University of Alabama at Birmingham (UAB)

Birmingham, Alabama, 35294, United States

Location

Northside Hospital, Inc.

Atlanta, Georgia, 30342, United States

Location

Northwestern Medical Hospital

Chicago, Illinois, 60611, United States

Location

The University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

Location

Northwell Health/Monter Cancer Center

Lake Success, New York, 11042, United States

Location

NYU Langone Medical Center

New York, New York, 10016, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Weill Cornell Medical Center

New York, New York, 10065, United States

Location

Stony Brook Cancer Center

Stony Brook, New York, 11794, United States

Location

Albert Einstein University / Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Vanderbilt-Ingham Cancer Center

Nashville, Tennessee, 37232, United States

Location

University of Wisconsin School of Medicine

Madison, Wisconsin, 53792-001, United States

Location

Related Links

• Herbert Irving Comprehensive Cancer Center (HICCC) Clinical Trials Page

MeSH Terms

Conditions

Breast Neoplasms

Interventions

ribociclib; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Melissa Accordino, MD
• Organization: Columbia University

mkg2134@cumc.columbia.edu

212-342-5162

Study Officials

• Melissa Accordino, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine, Division of Hematology/Oncology

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: December 16, 2015
• Study Start: March 1, 2016
• Primary Completion: January 4, 2022
• Study Completion: January 4, 2022
• Last Updated: December 6, 2024
• Results First Posted: December 6, 2024

Record last verified: 2024-12

Locations

US (13)