Clinical Trials /

Ribociclib (LEE011) in Preoperative Glioma and Meningioma Patients

NCT02933736

Description:

In the proposed trial, patients will be administered ribociclib prior to surgical resection of their tumor. Patients will be enrolled in time-intervals sequentially (non-randomized). All patients will be orally-administered 5 doses of LEE011 (900 mg/d) with the final dose occurring at one of 3 intervals before brain tumor resection.

Related Conditions:
  • Malignant Glioma
  • Meningioma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib (LEE011) in Preoperative Glioma and Meningioma Patients
  • Official Title: A Phase 0/II Study of Ribociclib (LEE011) in Preoperative Rb-Positive Recurrent High-Grade Glioma and Meningioma Patients Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration

Clinical Trial IDs

  • ORG STUDY ID: PHX-16-0116-80-12
  • NCT ID: NCT02933736

Conditions

  • Glioblastoma Multiforme
  • Meningioma

Interventions

DrugSynonymsArms
RibociclibLEE011Administration of ribociclib

Purpose

In the proposed trial, patients will be administered ribociclib prior to surgical resection of their tumor. Patients will be enrolled in time-intervals sequentially (non-randomized). All patients will be orally-administered 5 doses of LEE011 (900 mg/d) with the final dose occurring at one of 3 intervals before brain tumor resection.

Detailed Description

      900 mg/d is the maximally tolerated dose (MTD), as determined in a recent Novartis-sponsored
      Phase I study for advanced solid tumor patients. The recommended dose expansion and Phase 2
      is 600mg/d for 3 weeks on and 1 week off. Due to drug pharmacokinetics, the MTD (900mg) dose
      will be used for pre-surgical dosing in order to maximize the opportunity to identify
      relevant tumor pharmacokinetic (PK) and pharmacodynamics (PD) endpoints.

      To assess the PK, and PD endpoints listed above, cerebrospinal fluid (CSF) and brain tumor
      tissue will be collected intraoperatively (for gliomas, enhancing and non-enhancing tumor
      tissue will be collected and analyzed separately). Additionally, blood samples will be
      obtained at 0.5, 1, 2, 4, 6, 8, and 24 hours after the final ribociclib dose is administered.

      Patients with tumors demonstrating positive PK and PD effects will continue treatment with
      ribociclib (21 days on, 7 days off) after surgery. This will constitute the Phase II
      component of the study. Patients will be treated until unacceptable toxicity is observed, or
      until disease progression as assessed by radiographic or clinical metrics. Preliminary rates
      of progression-free survival in patients with high-grade gliomas and high-grade meningiomas
      treated with ribociclib will be measured through radiographic and clinical response metrics,
      specifically Response Assessment in Neuro-Oncology (RANO) criteria and investigator
      discretion. Overall survival in patients with high-grade gliomas and high-grade meningiomas
      treated with ribociclib will be assessed by medical record review and survival follow up.
    

Trial Arms

NameTypeDescriptionInterventions
Administration of ribociclibExperimentalSubjects will be administered ribociclib prior to surgical resection of their tumor. All patients will be orally-administered 5 doses of LEE011 (900 mg/d) with the final dose occurring at one of 3 following intervals before brain tumor resection: Cohort 1: last ribociclib dose 2-4 hours prior to craniotomy for tumor resection Cohort 2: last ribociclib dose 6-8 hours prior to craniotomy for tumor resection Cohort 3: last ribociclib dose 23-25 hours prior to craniotomy for tumor resection
  • Ribociclib

Eligibility Criteria

        Inclusion Criteria

          -  One prior resection of histologically-diagnosed World Health Organization (WHO) Grade
             III or IV glioma, or WHO grade II or III meningioma.

          -  MRI evidence of disease recurrence

          -  For gliomas, archival tissue must demonstrate: (a) RB positivity on
             immunohistochemistry OR no RB mutations on next-gen sequencing (NGS), (b) Chromosome
             9p21.3 deletion on FISH OR CDKN2A/B/C loss on array CGH OR CDK4/6 or CCND1/2
             amplification on array CGH.

          -  For meningiomas, archival tissue much demonstrate (a) RB positivity on
             immunohistochemistry OR no RB mutations on next-gen sequencing (NGS).

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2

          -  Patients ≥ 18 years of age

          -  Ability to understand and the willingness to sign a written informed consent document
             (personally or by the legally authorized representative, if applicable).

          -  Patient has voluntarily agreed to participate by giving written informed consent
             (personally or via legally-authorized representative(s), and assent if applicable).

        (Written informed consent for the protocol must be obtained prior to any screening
        procedures. If consent cannot be expressed in writing, it must be formally documented and
        witnessed, ideally via an independent trusted witness.)

          -  Patients must have recovered from all toxicities related to prior anticancer therapies
             to ≤ grade 2 (CTCAE v 4.03), provided that concomitant medication is given prior to
             initiation of treatment with ribociclib. Exception to this criterion: patients with
             any grade of alopecia are allowed to enter the treatment.

          -  The following laboratory criteria have been met:

               -  Absolute neutrophil count (ANC) ≥1.5 x 109/L

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Platelets ≥100 x 10^9/L

               -  Potassium, total calcium (corrected for serum albumin), magnesium, and sodium
                  within normal limits for the institution or corrected to within normal limits
                  with supplements before first dose of study medication.

               -  INR ≤1.5

               -  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 ULN.

          -  Serum total bilirubin < ULN, or < 3.0 x ULN in patients with well-documented Gilbert's
             syndrome.

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

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

               -  Resting heartrate 50-90 bpm

          -  Must be able to swallow ribociclib capsules/tablets

          -  If patient is receiving tamoxifen or toremifene, a washout period of 5 half-lives
             prior to enrollment is required

        Exclusion Criteria:

          -  Archival tissue not available for research use.

          -  Archival tumor not Rb-positive status

          -  No prior radiotherapy

          -  Co-morbid condition(s) that, at the opinion of the investigator, prevent safe surgical
             treatment

          -  Active infection or fever > 38.5°C

          -  Patients with known hypersensitivity to any of the excipients of ribociclib

          -  Patients with known hypersensitivity to peanut, soy or lactose

          -  Prior therapy with 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.

          -  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).

          -  History of HIV infection (testing not mandatory).

          -  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.

          -  Clinically significant, uncontrolled heart disease and/or cardiac repolarization
             abnormalities.

               -  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 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

          -  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, pomelos/pummelos, star-fruit, pomegranates or pomegranate juice and
                  Seville oranges

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

               -  Herbal preparations/medications, dietary supplements known as strong inhibitors
                  or inducers of CYP3A4 or those with a known risk of QT prolongation. (Does not
                  include Ca, Mg, Vit D or KCl supplements).

          -  Currently receiving warfarin or other coumarin-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.

          -  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).

          -  Has not recovered from all toxicities related to prior anticancer therapies to
             NCI-CTCAE version 4.03 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.).

          -  Child-Pugh score B or C.

          -  History of non-compliance to medical regimen.

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG laboratory test.]

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             during dosing and for 3 months after the last dose of study treatment. Highly
             effective contraception methods include:

               -  Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.
                  In case of oophorectomy alone, only when the reproductive status of the woman has
                  been confirmed by follow up hormone level assessment.

               -  Male sterilization (at least 6 months prior to screening) with the appropriate
                  post-vasectomy documentation of the absence of sperm in the ejaculate. For female
                  subjects on the study the vasectomized male partner should be the sole partner
                  for that subject.

               -  Use of oral, injected or implanted hormonal methods of contraception or placement
                  of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
                  hormonal contraception that have comparable efficacy (failure rate <1%), for
                  example hormone vaginal ring or transdermal hormone contraception.

               -  In case of use of oral contraception, women should have been stable on the same
                  pill for a minimum of 3 months before taking study treatment.

               -  Note: Oral contraceptives are allowed but should be used in conjunction with a
                  barrier method of contraception due to unknown effect of drug-drug interaction.

          -  Women are considered post-menopausal and not of child bearing potential if they have
             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
             In the case of oophorectomy alone, only when the reproductive status of the woman has
             been confirmed by follow up hormone level assessment is she considered not of child
             bearing potential.

          -  Sexually active males unless they use a condom during intercourse while taking 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:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Plasma Exposure
Time Frame:0.5, 1, 2, 4, 6, 8, and 24 hours post-last 900 mg dosing
Safety Issue:
Description:This is the Phase II portion, which assesses trough plasma concentrations of study drug on each clinical visit day, prior to administration of ribociclib on that day.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nader Sanai

Last Updated

May 12, 2020