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Ph0/2 Ribociclib & Everolimus

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ClinicalTrials.gov Identifier: NCT03834740
Recruitment Status : Recruiting
First Posted : February 8, 2019
Last Update Posted : February 8, 2019
Sponsor:
Collaborators:
Ivy Brain Tumor Center
Barrow Neurological Institute
Information provided by (Responsible Party):
St. Joseph's Hospital and Medical Center, Phoenix

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Glioma of Brain Drug: Ribociclib Drug: Everolimus 2.5 MG Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 21, 2018
Estimated Primary Completion Date : July 30, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Cohort 1: last dose 2 to 4 hours prior to resection

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)

Drug: Ribociclib
Ribociclib 400 mg administered orally in 5 daily doses prior to resection

Drug: Everolimus 2.5 MG
Everolimus 2.5mg administered orally in 5 daily doses prior to resection

Experimental: Cohort 2: last dose 8 to 10 hours prior to resection

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 2: last ribociclib+everolimus dose 8 to 10 hours prior to craniotomy for tumor resection (n=8 patients)

Drug: Ribociclib
Ribociclib 400 mg administered orally in 5 daily doses prior to resection

Drug: Everolimus 2.5 MG
Everolimus 2.5mg administered orally in 5 daily doses prior to resection

Experimental: Cohort 3: last dose 24 to 26 hours prior to resection

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 3: last ribociclib+everolimus dose 24 to 26 hours prior to craniotomy for tumor resection (n=8 patients)

Drug: Ribociclib
Ribociclib 400 mg administered orally in 5 daily doses prior to resection

Drug: Everolimus 2.5 MG
Everolimus 2.5mg administered orally in 5 daily doses prior to resection




Primary Outcome Measures :
  1. 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 ]
  2. Pharmacokinetic analysis - Total and Unbound Ribociclib and Everolimus Median concentration Cmax (0-24) [ Time Frame: Pre, 0.5, 1, 2, 4, 7, 24 hours post the last dose ]
  3. Pharmacokinetic analysis -Median concentration of Total Ribociclib and Everolimus Tmax [ Time Frame: 0-24 hours after the last dose ]
  4. Pharmacokinetic analysis - Total Ribociclib and Everolimus T1/2 (0-24) [ Time Frame: 0-24 hours after the last dose ]
  5. Pharmacokinetic analysis - Total and Unbound Ribociclib and Everolimus CL/F (0-24) [ Time Frame: 0-24 hours after the last dose ]
  6. Median concentration of ribociclib and everolimus for all patients for unbound plasma, CSF, Unbound NE, Unbound enhancing (2-24H post last dose) [ Time Frame: 2-24 hours after the last dose ]
  7. The percentage of pRB positive cells will be quantified in resected post-treatment recurrent tumor tissue compared to baseline (archival primary GBM tumor) [ Time Frame: Intraoperatively ]
  8. The percentage of pS6 positive cells will be quantified in resected post-treatment recurrent tumor tissue compared to baseline (archival primary GBM tumor) [ Time Frame: Intraoperatively ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. Number of Adverse Events [ Time Frame: Through study completion, assessed up to 60 months ]
  4. 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 ]

Other Outcome Measures:
  1. The median percentage of CDK4/6 and mTOR pathway active cells compared to baseline (total and phosphorylated forms of Rb, FoxM1, S6, 4EBP, as well as cleaved Caspase-3 and MIB1. Expression of Cyclin D1, Cyclin E1, PI3K/mTOR signaling components) [ Time Frame: baseline to intraoperative ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03834740


Contacts
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Contact: Jocelyn Harmon 602-406-3246 jocelyn.harmon@dignityhealth.org

Locations
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United States, Arizona
St. Joseph's Hospital and Medical Center Recruiting
Phoenix, Arizona, United States, 85013
Contact: Norissa Honea, PhD    602-406-6267    norissa.honea@dignityhealth.org   
Sponsors and Collaborators
St. Joseph's Hospital and Medical Center, Phoenix
Ivy Brain Tumor Center
Barrow Neurological Institute

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Responsible Party: St. Joseph's Hospital and Medical Center, Phoenix
ClinicalTrials.gov Identifier: NCT03834740     History of Changes
Other Study ID Numbers: 18-500-311-70-38
First Posted: February 8, 2019    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by St. Joseph's Hospital and Medical Center, Phoenix:
recurrent GBM
brain tumor
GBM
glioma

Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents