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.
- 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
- 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
- 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
- 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
- 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
- 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
- Inability to determine the QT interval on screening (QTcF, using Fridericia's
- 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
- That have a narrow therapeutic window and are predominantly metabolized through
- 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
- 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
- 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.