Clinical Trials /

Ribociclib and Letrozole in Treating Patients With Relapsed ER Positive Ovarian, Fallopian Tube, Primary Peritoneal, or Endometrial Cancer

NCT02657928

Description:

This phase II trial studies how well ribociclib and letrozole work in treating patients with estrogen receptor (ER) positive ovarian, fallopian tube, primary peritoneal, or endometrial cancer that has returned (come back) after a period of improvement. Ribociclib may stop the growth of tumor cells by blocking some enzymes needed for cell growth. Cancer cells that are estrogen receptor positive may need estrogen to grow. Letrozole lowers the amount of estrogen made by the body and this may stop the growth of tumor cells that need estrogen to grow. Giving ribociclib together with letrozole may be an effective treatment in patients with ovarian, fallopian tube, primary peritoneal, or endometrial cancer.

Related Conditions:
  • Endometrial Carcinoma
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib and Letrozole in Treating Patients With Relapsed ER Positive Ovarian, Fallopian Tube, Primary Peritoneal, or Endometrial Cancer
  • Official Title: A Phase 2 Trial of Ribociclib (LEE011) and Letrozole in ER Positive Relapsed Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Carcinomas, and Endometrial Cancers.

Clinical Trial IDs

  • ORG STUDY ID: MC1561
  • SECONDARY ID: NCI-2015-02181
  • SECONDARY ID: MC1561
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02657928

Conditions

  • Estrogen Receptor Positive
  • Postmenopausal
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Recurrent Uterine Corpus Carcinoma

Interventions

DrugSynonymsArms
LetrozoleCGS 20267, FemaraTreatment (ribociclib and letrozole)
RibociclibLEE-011, LEE011Treatment (ribociclib and letrozole)

Purpose

This phase II trial studies how well ribociclib and letrozole work in treating patients with estrogen receptor (ER) positive ovarian, fallopian tube, primary peritoneal, or endometrial cancer that has returned (come back) after a period of improvement. Ribociclib may stop the growth of tumor cells by blocking some enzymes needed for cell growth. Cancer cells that are estrogen receptor positive may need estrogen to grow. Letrozole lowers the amount of estrogen made by the body and this may stop the growth of tumor cells that need estrogen to grow. Giving ribociclib together with letrozole may be an effective treatment in patients with ovarian, fallopian tube, primary peritoneal, or endometrial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a higher
      percentage of patients who are progression free at 12 weeks (PFS 12) as compared with that
      observed in prior studies with single agent letrozole.

      SECONDARY OBJECTIVES:

      I. Demonstrate if the combination of letrozole and ribociclib (LEE011) leads to a higher
      cancer antigen 125 (CA-125) response rate in patients with relapsed ER positive ovarian
      cancers and endometrial cancers as compared to that observed in previously reported single
      agent letrozole studies.

      II. Median progression-free survival (PFS), overall survival (OS), the confirmed response
      rate, and adverse events.

      TERTIARY OBJECTIVES:

      I. Identify molecular biomarkers associated with a response to treatment with letrozole and
      ribociclib (LEE011) (in patients with relapsed ovarian carcinomas and endometrial cancers).

      II. Develop patient derived xenograft (PDX) avatars on tumors from participants for possible
      future translational study evaluating a potential correlation between responses in the PDX
      model to patients' responses.

      OUTLINE:

      Patients receive ribociclib orally (PO) daily and letrozole PO daily on days 1-28. Courses
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3-6 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ribociclib and letrozole)ExperimentalPatients receive ribociclib PO daily and letrozole PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Letrozole
  • Ribociclib

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Post-menopausal

          -  Histologically confirmed recurrent ovarian, fallopian tube or primary peritoneal
             carcinoma or endometrial cancer in post-menopausal women; NOTE: pure clear cell and
             pure mucinous carcinomas are ineligible; platinum sensitive, platinum resistant and
             platinum refractory disease are eligible; no limitations in the number of prior
             regimens

          -  Patient has disease amenable to biopsy and is agreeable to undergo a biopsy; NOTE:
             under unusual circumstances, submission of ascites material may be acceptable if a
             biopsy is not possible; this exception will require approval by one of the study
             principal investigators

          -  Willing to provide tissue samples for ER and retinoblastoma (RB) staining

          -  Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria

          -  Tumors must stain positive for estrogen receptor (>= 10%) by immunohistochemistry
             (IHC)

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Hemoglobin >= 9.0 g/dL

          -  Total bilirubin =< 1 x upper limit of normal (ULN); or total bilirubin =< 3.0 x ULN
             with direct bilirubin =< 1.5 x ULN in patients with well-documented Gilbert's syndrome

          -  Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (=< 5 x ULN in
             patients with liver metastasis)

          -  International normalized ratio (INR) =< 2

          -  Creatinine =< 1.5 mg/dL

          -  Potassium =< ULN (or corrected to =< ULN with supplements prior to registration)

          -  Total calcium (corrected for serum calcium) =< ULN (or corrected to =< ULN with
             supplements prior to registration)

          -  Magnesium =< ULN (or corrected to =< ULN with supplements prior to registration)

          -  Sodium =< ULN (or corrected to =< ULN with supplements prior to registration)

          -  Phosphorus =< ULN (or corrected to =< ULN with supplements prior to registration)

          -  Ability to swallow study medication

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

          -  Willing to provide tissue samples for correlative research purposes

        Exclusion Criteria:

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

               -  >= 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 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 or cardiac repolarization
             abnormalities and/or recent events 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

               -  Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
                  acquisition (MUGA) scan or echocardiogram (ECHO) at screening

               -  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 long QT syndrome

               -  Idiopathic sudden death or congenital long QT syndrome

               -  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 (corrected QT interval
                  [QTcF], using Fridericia's correction)

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

               -  Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse, at
                  screening

               -  Tachycardia (heart rate > 110 at rest), by ECG or pulse at screening

          -  Inability to determine the QTcF interval on the ECG (i.e.: unreadable or not
             interpretable) or QTcF > 450 msec (using Fridericia's correction); NOTE: all as
             determined by screening ECG

          -  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 cytochrome P450 family 3, subfamily A, polypeptide 4/5 (CYP3A4/5)
             including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges or
             that have a narrow therapeutic window and are predominantly metabolized through
             CYP3A4/5 or herbal preparations/medications or dietary supplements

          -  Patient is currently receiving or has received systemic corticosteroids within =< 2
             weeks prior to starting study drug, or who have not fully recovered from side effects
             of such treatment; NOTE: 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 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 >= 30% of the bone marrow was irradiated

          -  Patient has had major surgery =< 14 days prior to registration or has not recovered
             from major side effects (tumor biopsy is not considered as major surgery)

          -  Known to be human immunodeficiency virus (HIV) positive (testing not mandatory)

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

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

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

          -  Patient has not recovered from all toxicities related to prior anticancer therapies to
             National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE)
             version 4.0 grade < 3 (exception to this criterion: patients with any grade of
             alopecia or neuropathy are allowed to enter the study)

          -  Patient with a Child-Pugh score B or C

          -  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 significant small
             bowel resection)

          -  Prior therapy with ribociclib or an aromatase inhibitor (letrozole, anastrozole or
             exemestane)

          -  Patient has received systemic chemotherapy =< 3 weeks prior to registration
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients alive and progression-free at 12 weeks
Time Frame:At 12 weeks
Safety Issue:
Description:The proportion of progression-free at 12 weeks successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the exact binomial method.

Secondary Outcome Measures

Measure:CA-125 response, defined as a 50% or greater reduction in baseline CA-125
Time Frame:Up to 2 years
Safety Issue:
Description:The treatment of letrozole and ribociclib will be considered promising, based on CA-125, if the observed CA-125 response rate is 30% or more.
Measure:Confirmed response rate (complete response or partial response) using Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Incidence of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. Adverse events will be analyzed separately by cohort.
Measure:Overall survival
Time Frame:From registration to death from any cause, assessed up to 2 years
Safety Issue:
Description:Overall survival will be estimated using the method of Kaplan-Meier.
Measure:Progression-free survival
Time Frame:From registration to the first of either disease progression or death from any cause, assessed up to 2 years
Safety Issue:
Description:Progression-free survival will be estimated using the method of Kaplan-Meier.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Mayo Clinic

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