This is a Phase I/II study to assess the efficacy and safety of ribociclib in combination with topotecan and temozolomide (TOTEM) in pediatric patients with relapsed or refractory (r/r) neuroblastoma (NB), and other solid tumors, including medulloblastoma (MB), high-grade glioma (HGG), malignant rhabdoid tumors (MRT), and rhabdomyosarcoma (RMS).
The study is structured into two parts: Phase I - Part A (dose finding) and Phase I - Part B (multiple expansion cohorts). Phase II may commence following the evaluation of Phase I data, which includes safety, tolerability, efficacy, pharmacokinetics, and biomarker data. Additionally, other emerging data that could influence the treatment landscape will be considered before initiating Phase II in patients with relapsed or refractory neuroblastoma (NB) and/or other tumors studied in Phase I. \- Phase I - Part A (dose finding): This phase aims to determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM. Due to the early termination of the trial, Phase I - Part B (multiple expansion cohorts) and Phase II (double-blind, randomized, placebo-controlled in relapsed or refractory NB) were not initiated.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
Starting out dose of temozolomide for cohort A1 and A2 for Phase 1-Part A: 150mg/m2/day. Starting out dose for subsequent cohorts, Cohort A3 and onwards, in Phase 1-Part A will initiate at 100mg/m2/day.
Starting out dose of ribociclib for cohort A1 Phase 1-Part A: 200mg/m2/day. Starting out dose for Cohort A2 and A3 was 100mg/m2/day.
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Cohen Children's Medical Center of New York
New Hyde Park, New York, United States
St Jude s Childrens Research Hospital
Memphis, Tennessee, United States
Novartis Investigative Site
Cologne, Germany
Phase 1- Part A: Percentage of participants with Dose Limiting Toxicities (DLTs) in Cycle 1
Percentage of participants with DLTs during first cycle of treatment (each cycle is 28 days) for each dose level associated with administration of ribociclib in combination with topotecan and temozolomide. A DLT is defined as an adverse event or abnormal laboratory value suspected to be related with study treatment.
Time frame: Up to 28 days
Plasma concentrations of ribociclib (Phase I-Part A)
Pharmacokinetic (PK) blood samples will be collected at selected time-points to determine ribociclib plasma concentrations from participants in Phase I-Part A, Phase I-Part B and Phase II
Time frame: Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Area under the plasma concentration-time curve (AUC) of ribociclib (Phase I-Part A)
PK blood samples will be collected at selected time-points to determine AUC of ribociclib from participants in Phase I-Part A, Phase I-Part B and Phase II
Time frame: Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A)
PK blood samples will be collected at selected time-points to determine Cmax of ribociclib from participants in Phase I-Part A, Phase I-Part B and Phase II
Time frame: Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Time of maximum plasma concentration (Tmax) of ribociclib (Phase I-Part A)
PK blood samples will be collected at selected time-points to determine Cmax of ribociclib from participants in Phase I-Part A and Phase I-Part B.
Time frame: Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Percentage of participants with dose interruptions and dose reductions (Phase I-Part A)
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Novartis Investigative Site
Milan, MI, Italy
Novartis Investigative Site
Sutton, Surrey, United Kingdom
Percentage of participants with dose interruptions and dose reductions for participants in Phase I-Part A, Phase I-Part B and Phase II
Time frame: Up to 12 months