| Eligibility |
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. Recurrence must be confirmed by diagnostic biopsy with local pathology review or
contrast-enhanced MRI.
3. Subjects must have measurable disease preoperatively, defined as at least 1
contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per
RANO criteria.
4. 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.
5. Eastern Cooperative Oncology Group (ECOG) performance status =2 (Appendix 1)
6. Patients = 18 years of age
7. Ability to understand and the willingness to sign a written informed consent document.
(personally or by the legally authorized representative, if applicable).
8. Patient has voluntarily agreed to participate by giving written informed
consent.(personally or by the legally authorized representative, 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.)
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other procedures.
10. Confirmed negative serum pregnancy test (ß-hCG) before starting study treatment or
patient has had a hysterectomy.
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
- Estimated glomerular filtration rate (eGFR) = 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.
- Serum cholesterol < 300 mg/dL or < 7.75 mmol/L AND triclycerides < 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 (may be repeated up to 2x)
14. Must be able to swallow ribociclib and everolimus capsules/tablets
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.
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