Clinical Trials /

Ph0/2 Ribociclib & Everolimus

NCT03834740

Description:

In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical resection of their tumor. Recurrent GBM patients will be randomized into one of the three time-interval cohorts. All patients will receive ribociclib 400 mg and everolimus 2.5 mg (R2P2D) orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: - Cohort 1: last ribociclib+everolimus dose 2 to 4 hours prior to craniotomy for tumor resection (n=8 patients) - Cohort 2: last ribociclib+everolimus dose 8 to 10 hours prior to craniotomy for tumor resection (n=8 patients) - Cohort 3: last ribociclib+everolimus dose 24 to 26 hours prior to craniotomy for tumor resection (n=8 patients) To assess the PK and PD endpoints listed above, blood, CSF and brain tumor tissue will be collected intraoperatively (enhancing and non-enhancing tumor tissue will be collected and analyzed separately). Additionally, blood samples will be obtained on Day 4 (the day before the surgery for Cohorts 1 & 2; 2 days before surgery for Cohort 3) at pre-dosing (trough level), 0.5, 1, 2, 4, 7 hours post dose. A pre-dosing (trough level) blood sample will also be obtained on Day 5. Patients with tumors demonstrating favorable PK and PD will continue treatment with RP2D continuously in 28d cycles 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 treated with ribociclib+everolimus 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 treated with ribociclib+everolimus will be assessed by medical record review and survival follow up. Common Toxicity Criteria Adverse Event (CTC AE 4.03) will be utilized to review ribociclib+everolimus treatment effects in patients with brain tumors. In Phase II portion, trough steady-state blood samples will be obtained on days 1, 8, 15, and 22 of each cycle prior to the administration of ribociclib+everolimus on that day. Note: ribociclib+everolimus will be administered in the clinics on the clinic visit days to ensure the collection of trough level samples.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ph0/2 Ribociclib & Everolimus
  • Official Title: A Phase 0/II Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Rb-Intact Recurrent High-Grade Glioma Patients Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration

Clinical Trial IDs

  • ORG STUDY ID: 18-500-311-70-38
  • NCT ID: NCT03834740

Conditions

  • Glioblastoma Multiforme
  • Glioma of Brain

Interventions

DrugSynonymsArms
RibociclibCohort 1: last dose 2 to 4 hours prior to resection
Everolimus 2.5 MGCohort 1: last dose 2 to 4 hours prior to resection

Purpose

In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical resection of their tumor. Recurrent GBM patients will be randomized into one of the three time-interval cohorts. All patients will receive ribociclib 400 mg and everolimus 2.5 mg (R2P2D) orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: - Cohort 1: last ribociclib+everolimus dose 2 to 4 hours prior to craniotomy for tumor resection (n=8 patients) - Cohort 2: last ribociclib+everolimus dose 8 to 10 hours prior to craniotomy for tumor resection (n=8 patients) - Cohort 3: last ribociclib+everolimus dose 24 to 26 hours prior to craniotomy for tumor resection (n=8 patients) To assess the PK and PD endpoints listed above, blood, CSF and brain tumor tissue will be collected intraoperatively (enhancing and non-enhancing tumor tissue will be collected and analyzed separately). Additionally, blood samples will be obtained on Day 4 (the day before the surgery for Cohorts 1 & 2; 2 days before surgery for Cohort 3) at pre-dosing (trough level), 0.5, 1, 2, 4, 7 hours post dose. A pre-dosing (trough level) blood sample will also be obtained on Day 5. Patients with tumors demonstrating favorable PK and PD will continue treatment with RP2D continuously in 28d cycles 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 treated with ribociclib+everolimus 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 treated with ribociclib+everolimus will be assessed by medical record review and survival follow up. Common Toxicity Criteria Adverse Event (CTC AE 4.03) will be utilized to review ribociclib+everolimus treatment effects in patients with brain tumors. In Phase II portion, trough steady-state blood samples will be obtained on days 1, 8, 15, and 22 of each cycle prior to the administration of ribociclib+everolimus on that day. Note: ribociclib+everolimus will be administered in the clinics on the clinic visit days to ensure the collection of trough level samples.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: last dose 2 to 4 hours prior to resectionExperimentalAll patients will receive ribociclib 400 mg and everolimus 2.5 mg (R2P2D) orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: • Cohort 1: last ribociclib+everolimus dose 2 to 4 hours prior to craniotomy for tumor resection (n=8 patients)
  • Ribociclib
  • Everolimus 2.5 MG
Cohort 2: last dose 8 to 10 hours prior to resectionExperimentalAll patients will receive ribociclib 400 mg and everolimus 2.5 mg (R2P2D) orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: • Cohort 2: last ribociclib+everolimus dose 8 to 10 hours prior to craniotomy for tumor resection (n=8 patients)
  • Ribociclib
  • Everolimus 2.5 MG
Cohort 3: last dose 24 to 26 hours prior to resectionExperimentalAll patients will receive ribociclib 400 mg and everolimus 2.5 mg (R2P2D) orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: • Cohort 3: last ribociclib+everolimus dose 24 to 26 hours prior to craniotomy for tumor resection (n=8 patients)
  • Ribociclib
  • Everolimus 2.5 MG

Eligibility Criteria

        Inclusion Criteria:

          1. Prior resection of histologically-diagnosed WHO Grade III or IV glioma. A. Glioma
             patients who have progressed on or following standard (Stupp regimen) therapy, which
             included maximal surgical resection, temozolomide, and fractionated radiotherapy.

          2. Patient must have MRI evidence of disease recurrence

          3. For gliomas, archival tissue must demonstrate: (a) RB positivity (≥20%) on
             immunohistochemistry OR no RB mutations on next-generation sequencing (NGS), (b)
             Chromosomal loss of CDKN2A/B/C OR CDK4/6 or CCND1/2 amplification on array CGH, (c)
             mTOR+: PTEN loss OR PIK3C2B or AKT3 amplification on aCGH OR mutations for PIK3CA or
             PIK3R1, or mTOR or PTEN mutations using rhAMP analysis or pS6 positivity on
             immunohistochemistry (≥10% for pS6). If mutations within the mTOR/PI3K pathways cannot
             be accurately detected due to poor tissue quality the enrollment criteria will be
             determined using RB and pS6 positivity.

          4. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix 1)

          5. Patients ≥ 18 years of age

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

          7. Patient has voluntarily agreed to participate by giving written informed consent.

             (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.)

          8. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
             tests and other procedures.

          9. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or
             patient has had a hysterectomy.

         10. 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.

         11. Patient has adequate bone marrow and organ function as defined by the following
             laboratory values (as assessed by the local laboratory for eligibility):

               -  The following laboratory criteria have been met:

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

               -  Hemoglobin (Hgb) ≥ 9.0 g/dL

               -  Platelets ≥ 100 x 109/L

               -  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.

               -  INR ≤1.5 (unless the patient is receiving anticoagulants and the INR is within
                  the therapeutic range of intended use for that anticoagulant within 7 days prior
                  to the first dose of study drug)

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

               -  Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault
                  formula.

               -  In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
                  aminotransferase (AST) < 2.5 x ULN. If the patient has liver metastases, ALT and
                  AST < 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 triplicate ECGs):

               -  Fasting serum cholesterol < 300 mg/dL or < 7.75 mmol/L AND fasting triglycerides
                  < 2.5 x ULN (NOTE: in case one or both of these thresholds are exceeded, the
                  patient can only be included after initiation of appropriate lipid lowering
                  medication.)

         12. QTcF interval at screening < 450 msec [using Fridericia's correction (formula =
             QT/(RR)0.33)]

         13. Resting heart rate 50-90 bpm

         14. Must be able to swallow ribociclib and everolimus capsules/tablets

        Exclusion Criteria:

          1. Archival tissue is not available for research use or there is not a sufficient
             quantity available to confirm eligibility.

          2. Archival tumor is not Rb-positive status and mTOR-positive status

          3. Patient has not received prior radiotherapy

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

          5. Active infection or fever > 38.5°C

          6. Active (acute or chronic) or uncontrolled severe infection, liver disease such as
             cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.
             quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)

          7. Known severely impaired lung function (spirometry and DLCO 50% or less of normal and
             O2 saturation 88% or less at rest on room air)

          8. Active, bleeding diathesis

          9. Patients with known hypersensitivity to any of the excipients of ribociclib or mTOR
             inhibitors (sirolimus or everolimus), including peanut, soy and lactose

         10. Prior therapy with ribociclib

         11. 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

         12. 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

         13. 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)

         14. Patient has a known history of HIV infection (seropositivity; testing not mandatory)

         15. Patients who have received live attenuated vaccines within 1 week of start of
             everolimus and during the study. Patient should also avoid close contact with others
             who have received live attenuated vaccines. Examples of live attenuated vaccines
             include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,
             varicella and TY21a typhoid vaccines

         16. 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.)

         17. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy.
             Patients with a known history of impaired fasting glucose or diabetes mellitus (DM)
             may be included, however blood glucose and antidiabetic treatment must be monitored
             closely throughout the trial and adjusted as necessary

         18. 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 pectoris, 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

         19. Patient is currently receiving any of the following medications and cannot be
             discontinued 7 days prior to starting study drug (see Appendix 1 for details):

               -  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

         20. Patient is 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

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

         22. 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)

         23. Patient 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 any grade
             of alopecia are allowed to enter the study)

         24. Patient with a Child-Pugh score B or C

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

         26. 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.]

         27. 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

         28. 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:Pharmacokinetic analysis -Total and Unbound Ribociclib and Everolimus AUC (0-24)
Time Frame:Pre, 0.5, 1, 2, 4, 7, 24 hours post the last dose
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Median progression-free survival (PFS) from time of surgery to date of recurrence in Phase 2 patients
Time Frame:From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Safety Issue:
Description:
Measure:Median Overall Survival (OS) from time of surgery to date of recurrence in Phase 2 patients
Time Frame:From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Safety Issue:
Description:
Measure:Number of Adverse Events
Time Frame:Through study completion, assessed up to 60 months
Safety Issue:
Description:
Measure:Median concentration of trough plasma concentrations of Total Ribociclib and Total Everolimus in Phase 2
Time Frame:From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Safety Issue:
Description:

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Joseph's Hospital and Medical Center, Phoenix

Trial Keywords

  • recurrent GBM
  • brain tumor
  • GBM
  • glioma

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