Trial Outcomes & Findings for Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors (NCT NCT03387020)

Last Updated: 2021-08-27

Results Overview

Defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. Will be estimated using a Rolling-6 phase I design. Only patients who are evaluable for DLT will be consider for estimating of Maximum Tolerated Dose. Patient who were enrolled under Surgical cohort but received sufficient study defined treatment would also be evaluable for DLT.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

22 participants

Primary outcome timeframe

4 weeks

Results posted on

2021-08-27

Participant Flow

This is Phase I and Surgical study for children with retinoblastoma protein 1 (Rb1) positive recurrent or refractory central nervous system tumors. Patients were enrolled at Pediatric Brain Tumor Consortium member institutions. The first patient was enrolled on 03/13/2018 and the last patient was enrolled on 11/18/2019. Patients who were enrolled under Surgical study may also be eligible to receive subsequent Phase I defined treatment and evaluable for DLT.

Total 22 eligible patients were enrolled. 16 of them enrolled on the Phase I study and 6 on the surgical cohort. The 'Started' row includes patients who are eligible for the study. One patient in Phase I dose level 1 withdrew prior to protocol therapy and one patient in Surgical study was not eligible for subsequent protocol therapy. The 'Completed' row includes patients who completed all Phase I protocol therapy or who experienced a protocol defined endpoint which took them off therapy.

Participant milestones

Participant milestones
Measure	Phase I, Dose Level 1 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 120 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Phase I, Dose Level 2 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.
Overall Study STARTED	13	3	5
Overall Study Received Treatment	12	3	5
Overall Study COMPLETED	11	1	5
Overall Study NOT COMPLETED	2	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I, Dose Level 1 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 120 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Phase I, Dose Level 2 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.
Overall Study Adverse Event	0	2	0
Overall Study Withdrawal by Subject	2	0	0

Baseline Characteristics

Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I, Dose Level 1 n=13 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 120 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Phase I, Dose Level 2 n=3 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=5 Participants Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Total n=21 Participants Total of all reporting groups
Age, Continuous	10.4 years n=5 Participants	8.6 years n=7 Participants	10.8 years n=5 Participants	10.4 years n=4 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	7 Participants n=4 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	14 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	13 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	13 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment United States	13 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants	21 participants n=4 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: Patients who were evaluable for dose finding assessment were used to determine the MTD. Evaluable patients are those who were eligible, started treatment and either experienced a dose limiting toxicity during course 1 or received adequate amount of treatment and were followed adequately to be assessed for safety during course 1. Evaluable patients could be from either Phase I stratum or from Surgical stratum as long as they received sufficient protocol defined Phase I treatment.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=16 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Maximum Tolerated Dose of Ribociclib and Everolimus Ribociclib	120 mg/m^2/day	—	—	—
Maximum Tolerated Dose of Ribociclib and Everolimus Everolumus	1.2 mg/m^2/day	—	—	—

PRIMARY outcome

Timeframe: Surgical study: Prior to starting ribociclib (day -7 or -10), prior to ribociclib dose on days -5 & -2, day 0, and at the time of surgery

Population: Patients who were enrolled on surgical study and with tumor and matching plasma samples available.

Average tumor Ribociclib concentrations will be compared to plasma concentrations. The mean tumor-to-plasma ratio of Ribociclib at the time of surgery will be described.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=5 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Average Tumor and Plasma Concentrations of Ribociclib for the Surgical Study	14.6 ratio Interval 2.22 to 53.4	—	—	—

SECONDARY outcome

Timeframe: Up to 2 years

Population: Patients who received Phase I treatment were included in the analysis. One patient in Phase I study withdrew prior to beginning protocol therapy and one patient in Surgical study was not eligible to start Phase I treatment.

Number of patients with sustained objective responses will be reported by stratum and dose. Objective response refers to at least 50% reduction in 2 dimensional measurements of the tumor. In order to count towards this objective, any response needs to be sustained for at least 8 weeks.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=12 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 n=3 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=5 Participants Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Objective Responses (Complete Response + Partial Response)	0 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Up to 2 years

Population: Consented patients in surgical study with pre-treatment tumor and post-treatment tumor tissue available

For the surgical study, Ki67 will be evaluated in paired pre-treatment tumor (diagnostic) and post-treatment tumor (recurrent) tissue in consenting patients to assess percent change. The percent of Ki67 in tumor tissues will be measured and the result is presented as the percent of Ki67 in post-treatment tumor minus the percent of Ki67 measured in pre-treatment tumor.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=2 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Percent Change in ki67 Between Archival and Post-treatment Tissue	-20 Change of Percentage of Ki67 in Tumor Interval -35.0 to -5.0	—	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose, 1, 2, 4, 8, 24, 32 (day 1 course 1 only), & 48 (day 1 course 1 only) hours after dose on days 1 and 17 of course 1.

Population: Patients with blood samples collected for pharmacokinetic studies on days 1 and 17 of course 1 were included. Surgical patients who received Phase I treatment with samples collected were also included in Dose Level 1. There are total 17 patients received dose level 1 treatment and 3 patients received dose level 2 treatment.

Ribociclib plasma concentration-time data obtained from patients who received Phase I defined treatment will be modeled using compartmental approaches to estimate the AUC (hr\*μM) for each dose level on days 1 and 17 of course 1. Patients who were enrolled in the Surgical stratum but subsequently received Phase I defined treatment with PK data available will also be included in the analysis population. 5 patients from surgical stratum received dose level 1 treatment.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=16 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 n=15 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=3 Participants Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 n=2 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Ribociclib AUC (Area Under the Plasma Concentration Versus Time Curve) as Obtained From the Patients Who Received Phase I Defined Treatment	3.96 hr*uM Interval 2.6 to 11.2	10.3 hr*uM Interval 5.3 to 18.7	12.0 hr*uM Interval 5.4 to 13.4	10.15 hr*uM Interval 9.6 to 10.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose, 0.5 (course 2 only), 1, 1.5 (course 2 only), 2, 4, 6 (course 2 only), 8, 24 hours after dose on day 17 of course 1, and day 1 of course 2.

Population: Patients with blood samples collected for pharmacokinetic studies on day 17 of course 1 and day 1 of course 2 were included. Surgical patients who received Phase I treatment with samples collected were also included in Dose Level 1. There are total 17 patients received dose level 1 treatment and 3 patients received dose level 2 treatment. Analysis population only includes treated patients with corresponding PK data available.

Everolimus plasma concentration-time data obtained from patients who received Phase I defined treatment will be modeled using compartmental approaches to estimate the AUC (hr\*nM) for each dose level on day 17 of course 1 and day 1 of course 2. Patients who were enrolled in the Surgical stratum but subsequently received Phase I defined treatment with PK data available will also be included in the analysis population. 5 patients from surgical stratum received dose level 1 treatment.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=14 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 n=10 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=2 Participants Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 n=2 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Everolimus AUC (Area Under the Plasma Concentration Versus Time Curve) as Obtained From the Phase I Study	201 hr*nM Interval 52.7 to 399.0	80.1 hr*nM Interval 29.8 to 146.0	147.5 hr*nM Interval 119.0 to 176.0	59 hr*nM Interval 42.5 to 75.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose, 1, 2, 4, 8, 24, 32 (day 1 course 1 only), & 48 (day 1 course 1 only) hours after dose on days 1 and 17 of course 1.

Ribociclib plasma concentration-time data obtained from patients received Phase I defined treatment will be modeled using compartmental approaches to estimate the half-life (hrs) for each dose level on days 1 and 17 of course 1. Patients who were enrolled in the Surgical stratum but subsequently received Phase I defined treatment with PK data available will also be included in the analysis population. 5 patients from surgical stratum received dose level 1 treatment.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=16 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 n=15 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=3 Participants Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 n=2 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Ribociclib Half-Life as Obtained From the Phase 1 Study	11.7 hours Interval 8.0 to 18.0	8.9 hours Interval 7.3 to 17.3	8.5 hours Interval 8.4 to 13.9	7.5 hours Interval 5.5 to 9.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-dose, 0.5 (course 2 only), 1, 1.5 (course 2 only), 2, 4, 6 (course 2 only), 8, & 24 hours after dose on day 17 of course 1, and day 1 of course 2

Population: Patients with blood samples collected for pharmacokinetic studies on day 17 of course 1 and day 1 of course 2 were included. Surgical patients who received Phase I treatment with samples collected were also included in Dose Level 1. There are total 17 patients received dose level 1 treatment and 3 patients received dose level 2 treatment. The analysis population only includes patients with corresponding PK data available at that timepoint.

Everolimus plasma concentration-time data obtained from patients received Phase I defined treatment will be modeled using compartmental approaches to estimate the half-life (hrs) for each dose level on day 17 of course 1 and day 1 of course 2. Patients who were enrolled in the Surgical stratum but subsequently received Phase I defined treatment with PK data available will also be included in the analysis population. 5 patients from surgical stratum received dose level 1 treatment.

Outcome measures

Outcome measures
Measure	DLT Evaluable Set n=14 Participants Patients either from Phase I stratum and received treatment from beginning, or from Surgical stratum who subsequently received Phase I defined treatment would be evaluable for MTD as long as they received sufficient Phase I defined treatment. Of the patients enrolled in Phase I stratum, 11 of them were evaluable for dose finding assessment. Of the patients enrolled in Surgical stratum, 5 of them were evaluable for dose finding assessment. Therefore, we have total 16 patients evaluable for dose finding assessment, 11 from Phase I stratum and 5 from Surgical stratum.	Phase I, Dose Level 2 n=10 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=2 Participants Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.	Dose Level 2, Day 17 of Course 1 n=2 Participants Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day. Samples are collected on Day 17 of Course 1
Everolimus Half Life as Obtained From the Phase 1 Study	13.5 hours Interval 8.5 to 23.1	14.5 hours Interval 6.9 to 23.9	11.2 hours Interval 9.0 to 13.3	11.5 hours Interval 7.3 to 15.6

Adverse Events

Phase I, Dose Level 1

Serious events: 6 serious events

Other events: 12 other events

Deaths: 5 deaths

Phase I, Dose Level 2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Surgical

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I, Dose Level 1 n=12 participants at risk Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 120 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Phase I, Dose Level 2 n=3 participants at risk Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2 at 170 mg/m2/day, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses at 1.2 mg/m2/day	Surgical n=5 participants at risk Patients who are undergoing surgery also received ribociclib PO QD on days 7-10 at 120 mg/m2/day before surgery. Eligible patients were subsequently treated on Phase 1, Dose Level 1.
Gastrointestinal disorders Vomiting	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	33.3% 1/3 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
General disorders Disease progression	16.7% 2/12 • Number of events 2 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Infections and infestations Enterocolitis infectious	0.00% 0/12 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	33.3% 1/3 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Musculoskeletal and connective tissue disorders Muscle weakness left-sided	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor hemorrhage	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Nervous system disorders DECREASED VISUAL FIELDS	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Nervous system disorders Depressed level of consciousness	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	20.0% 1/5 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Nervous system disorders Edema cerebral	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Nervous system disorders Glossopharyngeal nerve disorder	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Nervous system disorders MOTOR APRAXIA	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Nervous system disorders Seizure	16.7% 2/12 • Number of events 4 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.
Respiratory, thoracic and mediastinal disorders Dyspnea	8.3% 1/12 • Number of events 1 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/3 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.	0.00% 0/5 • Up to 2 years after starting treatment Adverse events (AEs) were graded using CTCAE v5.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to Ribociclib or Everolimus and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. Two patients did not started phase I protocol defined therapy and were not counted as at risk.

Other adverse events

Additional Information

Dr. Arzu Onar-Thomas

St. Jude Children's Research Hospital

Phone: 901-595-5499

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigator Initiated Interventional Trial Agreement between Novartis and PBTC and Cincinnati Children's Hospital Medical Center.
Publication restrictions are in place

Restriction type: OTHER