Clinical Trials /

Ribociclib and Aromatase Inhibitor in Treating Older Participants With Hormone Receptor Positive Metastatic Breast Cancer

NCT03477396

Description:

This phase IIA trial studies the side effects of ribociclib and aromatase inhibitor and how well they work in treating participants with hormone receptor positive breast cancer that has spread to other places in the body. Ribociclib and aromatase inhibitors may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib and Aromatase Inhibitor in Treating Older Participants With Hormone Receptor Positive Metastatic Breast Cancer
  • Official Title: A Phase IIA Trial Assessing the Tolerability of Ribociclib in Combination With an Aromatase Inhibitor in Patients Aged 70 and Older With Hormone Receptor Positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 17471
  • SECONDARY ID: NCI-2018-00370
  • SECONDARY ID: 17471
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT03477396

Conditions

  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Progesterone Receptor Positive
  • Stage IV Breast Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
Aromatase InhibitorAndrostenedione Aromatase Inhibitor, Estrogen Synthase Inhibitor, Estrogen Synthetase InhibitorTreatment (ribociclib, aromatase inhibitor)
RibociclibKisqali, LEE-011, LEE011Treatment (ribociclib, aromatase inhibitor)

Purpose

This phase IIA trial studies the side effects of ribociclib and aromatase inhibitor and how well they work in treating participants with hormone receptor positive breast cancer that has spread to other places in the body. Ribociclib and aromatase inhibitors may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the safety and tolerability of the combination of ribociclib and an aromatase
      inhibitor in adults age 70 or older with hormone receptor positive metastatic breast cancer.

      SECONDARY OBJECTIVES:

      I. To describe the full toxicity profile including all grades. II. To estimate the rate of
      worst grades of myelosuppression (neutropenia, leukopenia, thrombocytopenia, and anemia),
      neutropenic fever, gastrointestinal (GI) side effects (nausea, diarrhea, decreased appetite,
      vomiting, stomatitis), fatigue, neuropathy, and thromboembolism.

      III. To describe rates of dose reductions, dose holds, and hospitalizations. IV. To estimate
      objective response rate and clinical benefit rate as defined by modified Response Evaluation
      Criteria in Solid Tumors (RECIST) (1.1) criteria.

      V. To estimate median progression-free and overall survival.

      EXPLORATORY OBJECTIVES:

      I. To estimate the rate of adherence to ribociclib. II. To explore factors other than
      chronologic age that can affect toxicity rates as identified using a cancer-specific
      geriatric assessment.

      III. To describe the results of the Was It Worth It (WIWI) and the results of the Overall
      Treatment Utility (OTU) Questionnaires.

      OUTLINE:

      Participants receive ribociclib orally (PO) once daily (QD) on days 1-21 and aromatase
      inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 30 days, then annually
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ribociclib, aromatase inhibitor)ExperimentalParticipants receive ribociclib orally PO QD on days 1-21 and aromatase inhibitor per treating investigator's discretion. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Aromatase Inhibitor
  • Ribociclib

Eligibility Criteria

        Inclusion Criteria:

          -  Patient has signed the informed consent (ICF) prior to any study procedures being
             performed and is able to comply with protocol requirements

          -  Absolute neutrophil count ≥ 1.5 x 10^9 /L

          -  Platelets ≥ 100 x 10^9 /L

          -  Hemoglobin ≥ 9.0 g/dL

          -  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

          -  Serum creatinine < 1.5 mg/dL or creatinine clearance ≥ 50 mL/min

          -  In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST) < 2.5 x upper limit of normal (ULN); if the patient has liver
             metastases, ALT and AST < 5 x ULN

          -  Total bilirubin < ULN; or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
             in patients with well-documented Gilbert's syndrome

          -  Patient with available standard 12-lead electrocardiogram (ECG) with the following
             parameters at screening (defined as the mean of the triplicate ECGs):

               -  Fridericia's corrected QT (QTcF) interval at screening < 450msec (using
                  Fridericia's correction)

               -  Resting heart rate 50-90 beats per minute (bpm)

          -  Must be able to swallow ribociclib

          -  ≥ 70 years at time of enrollment; ≥ 70 to < 74 years, ≥ 75 years

               -  NOTE: A minimum of 20 participants must be ≥ 75 years; the remaining 20
                  participants may be ≥ 70 to < 74 years OR ≥ 75 years

          -  Life expectancy > 6 months

          -  Ability to read and comprehend in English (for completion of questionnaires)

          -  Clinical and histological confirmation of hormone receptor positive, HER2 receptor
             negative metastatic breast cancer

          -  Measurable disease according to the Response Evaluation Criteria in Solid Tumors
             (RECIST 1.1), or bone-only lytic or mixed lytic and blastic lesions that would be
             accurately assessed by means of computed tomography (CT) or magnetic resonance imaging
             (MRI)

          -  First or second line endocrine therapy for metastatic disease; one prior line of
             chemotherapy for metastatic disease is allowed

          -  Resolution of all acute toxic effects of prior therapy or surgical procedures to
             Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 1 (except alopecia)
             prior to registration

        Exclusion Criteria:

          -  Patient has a known hypersensitivity to any of the excipients of ribociclib

          -  Patient has a concurrent malignancy or malignancy within 3 years prior to starting
             study drug, with the exception of adequately treated, basal or squamous cell
             carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer

          -  Patients with central nervous system (CNS) involvement unless they meet ALL the
             following criteria:

               -  At least 4 weeks from prior therapy completion (including radiation and/or
                  surgery) to starting the study treatment

               -  Clinically stable CNS tumor at the time of screening and not receiving steroids
                  and/or enzyme-inducing anti-epileptic medications for brain metastases

          -  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 human immunodeficiency virus (HIV) infection (testing
             not mandatory)

          -  Patient has any other concurrent severe and/or uncontrolled medical condition that
             would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
             patient participation in the clinical study or compromise compliance with the protocol
             (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled
             fungal, bacterial or viral infections, etc.)

          -  Clinically significant, uncontrolled heart disease and/or cardiac repolarization
             abnormalities, including any of the following:

               -  History of acute coronary syndromes (including myocardial infarction, unstable
                  angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
                  symptomatic pericarditis within 6 months prior to screening

               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)

               -  Documented cardiomyopathy

               -  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)

               -  Long QT syndrome or family history of idiopathic sudden death or congenital long
                  QT syndrome, or any of the following:

                    -  Risk factors for Torsades de pointe (TdP) including uncorrected hypokalemia
                       or hypomagnesemia, history of cardiac failure, or history of clinically
                       significant/symptomatic bradycardia

                    -  Concomitant use of medication(s) with a known risk to prolong the QT
                       interval and/or known to cause Torsades de pointe that cannot be
                       discontinued (within 5 half-lives or 7 days prior to starting study drug) or
                       replaced by safe alternative medication

                    -  Inability to determine the QT interval on screening (QTcF, using
                       Fridericia's correction)

               -  Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening

          -  Patient is currently receiving any of the following medications and cannot be
             discontinued 7 days prior to starting study drug:

               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
                  hybrids, pummelos, star-fruit, and Seville oranges

               -  That have a narrow therapeutic window and are predominantly metabolized through
                  CYP3A4/5

               -  Herbal preparations/medications, dietary supplements

          -  Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks
             prior to starting study drug, or who have not fully recovered from side effects of
             such treatment

               -  The following uses of corticosteroids are permitted: single doses, topical
                  applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways
                  diseases), eye drops or local injections (e.g., intra-articular)

          -  Patient is currently receiving warfarin or other coumadin-derived anticoagulant for
             treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight
             heparin (LMWH) or fondaparinux is allowed

          -  Participation in a prior investigational study within 30 days prior to enrollment or
             within 5 half-lives of the investigational product, whichever is longer

          -  Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for
             palliation ≤ 2 weeks prior to starting study drug, and who has not recovered to grade
             1 or better from related side effects of such therapy (exceptions include alopecia)
             and/or in whom ≥ 25% of the bone marrow (Ellis, 1961) was irradiated

          -  Patient has had major surgery within 14 days prior to starting study drug or has not
             recovered from major side effects (tumor biopsy is not considered as major surgery)

          -  Patient has not recovered from all toxicities related to prior anticancer therapies to
             National Cancer Institute (NCI)-CTCAE version 4.03 grade < 1 (exception to this
             criterion: patients with any grade of alopecia are allowed to enter the study)

          -  Patient with a Child-Pugh score B or C

          -  Patient has a history of non-compliance to medical regimen or inability to grant
             consent

          -  Sexually active males unless they use a condom during intercourse while taking the
             drug and for 21 days after stopping treatment and should not father a child in this
             period; a condom is required to be used also by vasectomized men in order to prevent
             delivery of the drug via seminal fluid
      
Maximum Eligible Age:N/A
Minimum Eligible Age:70 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of grade 2 and above toxicities attributed (possible or above) to ribociclib
Time Frame:Up to 30 days of last study drug
Safety Issue:
Description:Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.

Secondary Outcome Measures

Measure:Incidence of adverse events associated with the combinations as measured by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 2 years
Safety Issue:
Description:Tables will be created to summarize the toxicities and side effects by age strata, course, organ, severity and attribution for all patients.
Measure:Dose reductions
Time Frame:Up to 2 years
Safety Issue:
Description:Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.
Measure:Dose delays
Time Frame:Up to 2 years
Safety Issue:
Description:Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.
Measure:Dose discontinuations
Time Frame:Up to 2 years
Safety Issue:
Description:Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.
Measure:Objective response rate (defined as complete response [CR] + partial response [PR]) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.
Measure:Clinical benefit rate (defined as CR+PR+ stable disease) as determined by RECIST
Time Frame:Up to 2 years
Safety Issue:
Description:Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.
Measure:Progression free survival defined as the time from start of treatment to the first of the following disease events: local/regional/distant recurrence, invasive contralateral breast disease, second primary or death due to any cause
Time Frame:From start of treatment up to 2 years
Safety Issue:
Description:Will be estimated using the product limit method of Kaplan and Meier/ Cox proportional hazards methods.
Measure:Overall survival defined as the time from start of treatment to death due to any cause
Time Frame:From start of treatment up to 2 years
Safety Issue:
Description:Will be estimated using the product limit method of Kaplan and Meier/ Cox proportional hazards methods.
Measure:Average plasma steady-state ribociclib C trough concentrations in patients over the age of 70 years
Time Frame:Up to 2 years
Safety Issue:
Description:The relationship between plasma trough and percent drop in neutrophil counts using linear models.
Measure:Average plasma steady-state ribociclib C trough concentrations in patients over the age of 70 years
Time Frame:Up to 2 years
Safety Issue:
Description:The relationship between plasma trough and percent drop in platelet counts using linear models.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

March 19, 2018