NCT03387020

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

Completed Phase 1 Results posted Last updated 27 August 2021

What this trial tests

Phase 1 trial testing Everolimus in CNS Embryonal Tumor, Not Otherwise Specified in 22 participants. Completed in 1 April 2020.

Timeline

13 January 2018

Primary endpoint
1 April 2020

1 April 2020

Quick facts

Lead sponsor	Pediatric Brain Tumor Consortium
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	22
Start date	13 January 2018
Primary completion	1 April 2020
Estimated completion	1 April 2020
Sites	12 locations across United States

Drugs / interventions tested

• Everolimus (everolimus) — full drug profile →
• Laboratory Biomarker Analysis
• Pharmacological Study — full drug profile →
• Ribociclib (ribociclib) — full drug profile →

Conditions studied

• CNS Embryonal Tumor, Not Otherwise Specified — all drugs for CNS Embryonal Tumor, Not Otherwise Specified →
• Malignant Glioma — all drugs for Malignant Glioma →
• Recurrent Atypical Teratoid/Rhabdoid Tumor — all drugs for Recurrent Atypical Teratoid/Rhabdoid Tumor →
• Recurrent Childhood Ependymoma — all drugs for Recurrent Childhood Ependymoma →

Sponsor

Pediatric Brain Tumor Consortium

Who can join

Adults 1 to 21, any sex, with CNS Embryonal Tumor, Not Otherwise Specified or Malignant Glioma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximum Tolerated Dose of Ribociclib and Everolimus Primary · 4 weeks

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.

Ribociclib

Group	Value	95% CI
DLT Evaluable Set	120

Everolumus

Group	Value	95% CI
DLT Evaluable Set	1.2

Average Tumor and Plasma Concentrations of Ribociclib for the Surgical Study Primary · 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

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.

Group	Value	95% CI
Surgical	14.6	2.22 – 53.4

Objective Responses (Complete Response + Partial Response) Secondary · Up to 2 years

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.

Group	Value	95% CI
Phase I, Dose Level 1	0
Phase I, Dose Level 2	0
Surgical	0

Percent Change in ki67 Between Archival and Post-treatment Tissue Secondary · Up to 2 years

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.

Group	Value	95% CI
Surgical	-20	-35 – -5

Ribociclib AUC (Area Under the Plasma Concentration Versus Time Curve) as Obtained From the Patients Who Received Phase I Defined Treatment Secondary · 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 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.

Group	Value	95% CI
Dose Level 1, Day 1 of Course 1	3.96	2.6 – 11.2
Dose Level 1, Day 17 of Course 1	10.3	5.3 – 18.7
Dose Level 2, Day 1 of Course 1	12.0	5.4 – 13.4
Dose Level 2, Day 17 of Course 1	10.15	9.6 – 10.7

Everolimus AUC (Area Under the Plasma Concentration Versus Time Curve) as Obtained From the Phase I Study Secondary · 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.

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.

Group	Value	95% CI
Dose Level 1, Day 17 of Course 1	201	52.7 – 399
Dose Level 1, Day 1 of Course 2	80.1	29.8 – 146
Dose Level 2, Day 17 of Course 1	147.5	119 – 176
Dose Level 2, Day 1 of Course 2	59	42.5 – 75.5

Ribociclib Half-Life as Obtained From the Phase 1 Study Secondary · 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.

Group	Value	95% CI
Dose Level 1, Day 1 of Course 1	11.7	8.0 – 18.0
Dose Level 1, Day 17 of Course 1	8.9	7.3 – 17.3
Dose Level 2, Day 1 of Course 1	8.5	8.4 – 13.9
Dose Level 2, Day 17 of Course 1	7.5	5.5 – 9.5

Everolimus Half Life as Obtained From the Phase 1 Study Secondary · 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

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.

Group	Value	95% CI
Dose Level 1, Day 17 of Course 1	13.5	8.5 – 23.1
Dose Level 1, Day 1 of Course 2	14.5	6.9 – 23.9
Dose Level 2, Day 17 of Course 1	11.2	9.0 – 13.3
Dose Level 2, Day 1 of Course 2	11.5	7.3 – 15.6

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 2 years after starting treatment. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase I, Dose Level 1

Serious: 6/12 (50%)

Deaths: 5/12

Phase I, Dose Level 2

Serious: 1/3 (33%)

Deaths: 0/3

Surgical

Serious: 1/5 (20%)

Deaths: 0/5

Serious adverse events (12 terms)

Reaction	System	Phase I, Dose Level 1	Phase I, Dose Level 2	Surgical
Disease progression	General disorders	—	—	—
Seizure	Nervous system disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Enterocolitis infectious	Infections and infestations	—	—	—
Muscle weakness left-sided	Musculoskeletal and connective tissue disorders	—	—	—
Tumor hemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
DECREASED VISUAL FIELDS	Nervous system disorders	—	—	—
Depressed level of consciousness	Nervous system disorders	—	—	—
Edema cerebral	Nervous system disorders	—	—	—
Glossopharyngeal nerve disorder	Nervous system disorders	—	—	—
MOTOR APRAXIA	Nervous system disorders	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—

Other adverse events (42 terms — click to expand)

Reaction	System	Phase I, Dose Level 1	Phase I, Dose Level 2	Surgical
Fatigue	General disorders	—	—	—
White blood cell decreased	Investigations	—	—	—
Neutrophil count decreased	Investigations	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Cholesterol high	Investigations	—	—	—
Lymphocyte count decreased	Investigations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Platelet count decreased	Investigations	—	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Weight loss	Investigations	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—
Hypertriglyceridemia	Metabolism and nutrition disorders	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—
Ataxia	Nervous system disorders	—	—	—
Headache	Nervous system disorders	—	—	—
PEDIATRIC HYPERTENSION	Vascular disorders	—	—	—
Corneal ulcer	Eye disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Edema limbs	General disorders	—	—	—
Pain	General disorders	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—
Creatinine increased	Investigations	—	—	—
Electrocardiogram QT corrected interval prolonged	Investigations	—	—	—
Weight gain	Investigations	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—
DISEASE PROGRESSION	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Dysgeusia	Nervous system disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Irritability	Psychiatric disorders	—	—	—

Most-reported serious reactions: Disease progression, Seizure, Vomiting, Enterocolitis infectious, Muscle weakness left-sided, Tumor hemorrhage, DECREASED VISUAL FIELDS, Depressed level of consciousness.

Data from ClinicalTrials.gov NCT03387020 adverse events section.

Sponsor's own description

This phase I trial studies the side effects and best dose of ribociclib and everolimus and to see how well they work in treating patients with malignant brain tumors that have come back or do not respond to treatment. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib and everolimus may work better at treating malignant brain tumors.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies.
   Findlay IJ, De Iuliis GN, Duchatel RJ, Jackson ER, et al · · 2022 · cited 77× · PMID 34759345 · DOI 10.1038/s41388-021-02102-y
2. Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review.
   Gallitto M, Lazarev S, Wasserman I, Stafford JM, et al · · 2019 · cited 73× · PMID 31360809 · DOI 10.1016/j.adro.2019.03.009
3. Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches.
   Menyhárt O, Győrffy B. · · 2020 · cited 60× · PMID 31970590 · DOI 10.1007/s10555-020-09854-1
4. Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force.
   Bailey K, Cost C, Davis I, Glade-Bender J, et al · · 2019 · cited 58× · PMID 31031965 · DOI 10.12688/f1000research.18139.1
5. Atypical teratoid rhabdoid tumor: molecular insights and translation to novel therapeutics.
   Nesvick CL, Lafay-Cousin L, Raghunathan A, Bouffet E, et al · · 2020 · cited 51× · PMID 33021733 · DOI 10.1007/s11060-020-03639-w
6. Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors.
   Lake JA, Donson AM, Prince E, Davies KD, et al · · 2020 · cited 49× · PMID 31595628 · DOI 10.1002/pbc.28028
7. Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle.
   Di Ruscio V, Del Baldo G, Fabozzi F, Vinci M, et al · · 2022 · cited 34× · PMID 36140466 · DOI 10.3390/diagnostics12092064
8. A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study.
   DeWire MD, Fuller C, Campagne O, Lin T, et al · · 2021 · cited 27× · PMID 33547201 · DOI 10.1158/1078-0432.ccr-20-4078