A Phase 0/I Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Recurrent High-Grade Glioma Patients Scheduled for Resection

Exclusion Criteria

• •Patients eligible must not meet any of the following 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. Patients with a clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.
• •11. Prior therapy with ribociclib or any CDK4/6 inhibitor (e.g. palbociclib, abemaciclib), or with everolimus
• •12. 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 or other toxicities not considered a safety risk for the patient at investigator's discretion) and/or in whom ≥25% of the bone marrow (Ellis, 1961) was irradiated
• •13. 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
• •14. 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)
• •15. Patient has a known history of HIV infection (seropositivity; testing not mandatory)
• •16. 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
• •17. 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.)
• •18. Uncontrolled diabetes mellitus as defined by HbA1c \>8% despite adequate therapy as indicated by the medical history. 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
• •19. 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 (may be repeated up to 2x).
• •20. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug (see Appendix 2 for details):
• •* Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, 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)
• •* Known strong inhibitors or inducers of P-gp
• •21. Patients taking ACE inhibitors
• •22. 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
• •23. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
• •24. 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)
• •25. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 Grade ≤2 (Exception to this criterion: patients with any grade of alopecia and amenorrhea are allowed to enter the study)
• •26. Patient with a Child-Pugh score B or C
• •27. Patient has a history of non-compliance to medical regimen or inability to grant consent
• •28. 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.\]
• •29. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unwilling to use 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
• •30. Sexually active males unwilling to 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.