Glioblastoma Multiforme, Glioma of Brain
Conditions
Keywords
recurrent GBM, brain tumor, GBM, glioma
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 for the first two dose levels. In the lead-in dose escalation study, the first six subjects (lead-in) will receive ribociclib 400 mg and everolimus 2.5 mg orally-administered in 5 daily doses with the last dose. If one or less patient experiences DLT among the 6 patients, this regimen with ribociclib 400 mg and everolimus 2.5mg will be considered safe and we will continue with the dose escalation phase of the study up to Level 3. Four dose escalation levels: Level 0: ribociclib 400mg and everolimus 2.5 Level 1: ribociclib 600mg and everolimus 2.5mg Level 2: ribociclib 600mg and everolimus 5mg Level 3: ribociclib 600mg and everolimus 10mg
Interventions
DRUGRibociclib
Ribociclib administered orally in 5 daily doses prior to resection
DRUGEverolimus
Everolimus administered orally in 5 daily doses prior to resection
Sponsors
Ivy Brain Tumor Center
Barrow Neurological Institute
St. Joseph's Hospital and Medical Center, Phoenix
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 (β-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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | Baseline, Intraoperatively | The percentage change of pS6 positive cells in resected post-treatment recurrent GBM tumor tissue compared to baseline (archival primary GBM tumor tissue collected at screening). A positive PD effect is defined as \>30% decrease in pS6+ cells. |
| Pharmacokinetic Analysis - Total Everolimus Concentration | 0-24 hours after the last dose | Total everolimus concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis |
| Pharmacokinetic Analysis - Unbound Everolimus Concentration | 0-24 hours after the last dose | Unbound everolimus concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis |
| % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | Baseline, Intraoperatively | The percentage change of pRB positive cells in resected post-treatment recurrent GBM tumor tissue compared to baseline (archival primary GBM tumor tissue collected at screening). A positive PD effect is defined as \>30% decrease in pRB+ cells. |
| Maximum Tolerated Dose (MTD) | From the date of the first dose given until the second documented DLT, assessed up to 24 months | Highest dose of each drug that did not cause a DLT in \>17% of participants |
| Pharmacokinetic Analysis - Total Ribociclib Concentration | 0-24 hours after the last dose | Total ribociclib concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis |
| Pharmacokinetic Analysis - Unbound Ribociclib Concentration | 0-24 hours after the last dose | Unbound ribociclib concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival (OS) in Phase 2 Participants | From date of surgery to date of death from any cause, assessed up to 60 months | From date of surgery to date of death from any cause, assessed up to 60 months |
| Median Concentration of Trough Plasma Concentrations of Total Ribociclib and Total Everolimus in Phase 2 Participants | 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 | 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 |
| Median Progression-Free Survival (PFS) in Phase 2 Participants | 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 | 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 |
Countries
United States
Participant flow
Pre-assignment details
27 enrolled participants were assigned to 1 of 7 different dose escalation levels of ribociclib plus everolimus. For all levels, ribo doses were administered orally QD for five days. For levels 0-3, eve doses were administered orally QD for five days. For levels 4-6, a single dose of eve was administered once on day 5. Participants were also assigned to 1 of 3 time interval cohorts, each with a different timing for the administration of the final dose combination before brain tumor resection.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 0: Ribo 400mg+Eve 2.5mg QD Dose Level 0: Ribo 400mg+Eve 2.5mg QD and all 3 Time Cohorts were combined | 6 |
| Dose Level 1: Ribo 600mg+Eve 2.5mg QD Dose Level 1: Ribo 600mg+Eve 2.5mg QD of participants in both Time Cohorts 1 and 2 as only 1 participant in Time Cohort 1 at this dose level | 3 |
| Dose Level 2: Ribo 600mg+Eve 5mg QD Dose Level 2: Ribo 600mg+Eve 5mg QD of participants in Time Cohort 2 | 3 |
| Dose Level 3: Ribo 600mg+Eve 10mg QD Dose Level 3: Ribo 600mg+Eve 10mg QD of participants in Time Cohort 2 | 4 |
| Dose Level 4: Ribo 600mg QD+Eve 50mg Once Dose Level 4: Ribo 600mg QD+Eve 50mg Once of participants in Time Cohort 2 | 4 |
| Dose Level 5: Ribo 600mg QD+Eve 60mg Once Dose Level 5: Ribo 600mg QD+Eve 60mg Once of participants in Time Cohort 2 | 3 |
| Dose Level 6: Ribo 600mg QD+Eve 70mg Once Dose Level 6: Ribo 600mg QD+Eve 70mg Once of participants in Time Cohort 2 | 4 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Ribo 600mg QD+Eve 70mg Once | Physician Decision | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Level 1: Ribo 600mg+Eve 2.5mg QD | Dose Level 2: Ribo 600mg+Eve 5mg QD | Dose Level 3: Ribo 600mg+Eve 10mg QD | Dose Level 4: Ribo 600mg QD+Eve 50mg Once | Dose Level 5: Ribo 600mg QD+Eve 60mg Once | Dose Level 6: Ribo 600mg QD+Eve 70mg Once | Dose Level 0: Ribo 400mg+Eve 2.5mg QD | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 20 Participants |
| Age, Continuous | 58 Years | 65 Years | 54.5 Years | 68 Years | 61 Years | 49 Years | 54 Years | 58 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants | 4 Participants | 6 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 26 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants | 2 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 3 / 6 | 3 / 3 | 1 / 3 | 3 / 4 | 2 / 4 | 2 / 3 | 3 / 4 |
| serious Total, serious adverse events | 0 / 6 | 3 / 3 | 1 / 3 | 0 / 4 | 1 / 4 | 1 / 3 | 1 / 4 |
Outcome results
Primary
% Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue
The percentage change of pRB positive cells in resected post-treatment recurrent GBM tumor tissue compared to baseline (archival primary GBM tumor tissue collected at screening). A positive PD effect is defined as \>30% decrease in pRB+ cells.
Time frame: Baseline, Intraoperatively
Population: 3 participants of 27 enrolled were not included in analysis due to pseudoprogression (dose levels 3, 4, and 6), and an additional 1 participant was excluded due to insufficient tumor content in the resected tissue sample (dose level 6).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 34 Percentage Change of pRB+ Cells |
| Ribociclib 600mg Dose | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 25 Percentage Change of pRB+ Cells |
| Everolimus 10mg Dose | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 268 Percentage Change of pRB+ Cells |
| Everolimus 50mg Dose | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -88 Percentage Change of pRB+ Cells |
| Everolimus 60mg Dose | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -64 Percentage Change of pRB+ Cells |
| Everolimus 70mg Dose | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -80 Percentage Change of pRB+ Cells |
| Dose Level 6: Ribo 600mg QD+Eve 70mg Once | % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 96 Percentage Change of pRB+ Cells |
Primary
% Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue
The percentage change of pS6 positive cells in resected post-treatment recurrent GBM tumor tissue compared to baseline (archival primary GBM tumor tissue collected at screening). A positive PD effect is defined as \>30% decrease in pS6+ cells.
Time frame: Baseline, Intraoperatively
Population: 3 participants of 27 enrolled were not included in analysis due to pseudoprogression (dose levels 3, 4, and 6) and an additional 1 participant was excluded due to insufficient tumor content in the resected tissue sample (dose level 6).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 242 Percentage Change of pS6+ Cells |
| Ribociclib 600mg Dose | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -10 Percentage Change of pS6+ Cells |
| Everolimus 10mg Dose | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 330 Percentage Change of pS6+ Cells |
| Everolimus 50mg Dose | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -8 Percentage Change of pS6+ Cells |
| Everolimus 60mg Dose | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | 431 Percentage Change of pS6+ Cells |
| Everolimus 70mg Dose | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -17 Percentage Change of pS6+ Cells |
| Dose Level 6: Ribo 600mg QD+Eve 70mg Once | % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue | -74 Percentage Change of pS6+ Cells |
Primary
Maximum Tolerated Dose (MTD)
Highest dose of each drug that did not cause a DLT in \>17% of participants
Time frame: From the date of the first dose given until the second documented DLT, assessed up to 24 months
Population: Enrolled participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Maximum Tolerated Dose (MTD) | Everolimus, once weekly | 70 milligrams |
| All Participants | Maximum Tolerated Dose (MTD) | Ribociclib, once daily | 600 milligrams |
Primary
Pharmacokinetic Analysis - Total Everolimus Concentration
Total everolimus concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis
Time frame: 0-24 hours after the last dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Pharmacokinetic Analysis - Total Everolimus Concentration | Non-Enhancing Tissue | 2.9 nanomolar |
| All Participants | Pharmacokinetic Analysis - Total Everolimus Concentration | Enhancing Tissue | 4.4 nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Non-Enhancing Tissue | 10.3 nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Enhancing Tissue | 16.6 nanomolar |
| Everolimus 10mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Non-Enhancing Tissue | 4.75 nanomolar |
| Everolimus 10mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Enhancing Tissue | 14.1 nanomolar |
| Everolimus 50mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Non-Enhancing Tissue | 6.3 nanomolar |
| Everolimus 50mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Enhancing Tissue | 53.05 nanomolar |
| Everolimus 60mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Non-Enhancing Tissue | 13.8 nanomolar |
| Everolimus 60mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Enhancing Tissue | 30.4 nanomolar |
| Everolimus 70mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Non-Enhancing Tissue | 8.2 nanomolar |
| Everolimus 70mg Dose | Pharmacokinetic Analysis - Total Everolimus Concentration | Enhancing Tissue | 71.8 nanomolar |
Primary
Pharmacokinetic Analysis - Total Ribociclib Concentration
Total ribociclib concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis
Time frame: 0-24 hours after the last dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Pharmacokinetic Analysis - Total Ribociclib Concentration | Non-Enhancing Tissue | 3132 nanomolar |
| All Participants | Pharmacokinetic Analysis - Total Ribociclib Concentration | Enhancing Tissue | 4056 nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Total Ribociclib Concentration | Non-Enhancing Tissue | 8193 nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Total Ribociclib Concentration | Enhancing Tissue | 14142 nanomolar |
Primary
Pharmacokinetic Analysis - Unbound Everolimus Concentration
Unbound everolimus concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis
Time frame: 0-24 hours after the last dose
Population: Results are below the lower limit of quantitation (BLQ) (\< 0.1 nM)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Non-Enhancing Tissue | NA nanomolar |
| All Participants | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Enhancing Tissue | NA nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Non-Enhancing Tissue | NA nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Enhancing Tissue | NA nanomolar |
| Everolimus 10mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Non-Enhancing Tissue | NA nanomolar |
| Everolimus 10mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Enhancing Tissue | NA nanomolar |
| Everolimus 50mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Non-Enhancing Tissue | NA nanomolar |
| Everolimus 50mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Enhancing Tissue | NA nanomolar |
| Everolimus 60mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Non-Enhancing Tissue | NA nanomolar |
| Everolimus 60mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Enhancing Tissue | NA nanomolar |
| Everolimus 70mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Non-Enhancing Tissue | NA nanomolar |
| Everolimus 70mg Dose | Pharmacokinetic Analysis - Unbound Everolimus Concentration | Enhancing Tissue | NA nanomolar |
Primary
Pharmacokinetic Analysis - Unbound Ribociclib Concentration
Unbound ribociclib concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis
Time frame: 0-24 hours after the last dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Pharmacokinetic Analysis - Unbound Ribociclib Concentration | Non-Enhancing Tissue | 170 nanomolar |
| All Participants | Pharmacokinetic Analysis - Unbound Ribociclib Concentration | Enhancing Tissue | 375 nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Unbound Ribociclib Concentration | Non-Enhancing Tissue | 634 nanomolar |
| Ribociclib 600mg Dose | Pharmacokinetic Analysis - Unbound Ribociclib Concentration | Enhancing Tissue | 1017 nanomolar |
Secondary
Median Concentration of Trough Plasma Concentrations of Total Ribociclib and Total Everolimus in Phase 2 Participants
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
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
Population: No participants were eligible for Phase 2 enrollment
Secondary
Median Overall Survival (OS) in Phase 2 Participants
From date of surgery to date of death from any cause, assessed up to 60 months
Time frame: From date of surgery to date of death from any cause, assessed up to 60 months
Population: No participants were eligible for Phase 2 enrollment
Secondary
Median Progression-Free Survival (PFS) in Phase 2 Participants
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
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
Population: No participants were eligible for Phase 2 enrollment