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Study of Efficacy and Safety of Ribociclib (LEE011) in Combination With Topotecan and Temozolomide (TOTEM) in Pediatric Patients With Relapsed or Refractory Neuroblastoma and Other Solid Tumors
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).
Study details:
The study consists of Phase I -part A (dose finding) and Phase I - part B (multiple expansion cohorts). Phase II may begin after evaluation of Phase I data (safety, tolerability, efficacy, pharmacokinetics and biomarker data), with consideration of other emerging data that may impact on the treatment landscape, before initiating Phase II in patients with relapsed or refractory NB and/or other tumors studied in Phase I. * Phase I-Part A (dose finding): a dose finding to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.
* Phase I- Part B (multiple expansion cohorts): it will be initiated to confirm RP2D identified from Phase I-part A. Multiple expansion cohorts have been planned to assess the preliminary antitumor activity and safety of ribociclib in combination with TOTEM in participants with r/r NB (cohort 1), MB (cohort 2), HGG (cohort 3), MRT (cohort 4), and RMS (cohort 5). * Phase II- Double-blind, randomized, placebo controlled in r/r NB: It is a two-arm randomized, double blinded, placebo controlled, parallel group trial in participants with r/r NB.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 12 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2022-12-27
Primary completion: 2029-02-28
Study completion finish: 2029-02-28
Study type
TREATMENT
Phase
PHASE1
PHASE2
Trial ID
NCT05429502
Intervention or treatment
DRUG: Topotecan
DRUG: Temozolomide
DRUG: Ribociclib
Conditions
- • Neuroblastoma
Find a site
Closest Location:
Novartis Investigative Site
Research sites nearby
Select from list below to view details:
Novartis Investigative Site
Randwick, New South Wales, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Participant Group/Arm | Intervention/Treatment |
---|---|
EXPERIMENTAL: Phase I-part A: Ribociclib + Topotecan and Temozolomide
| DRUG: Topotecan
|
EXPERIMENTAL: Phase I- Part B: r/r NB Cohort
| DRUG: Topotecan
|
EXPERIMENTAL: Phase I- Part B: r/r MB Cohort
| DRUG: Topotecan
|
EXPERIMENTAL: Phase I-Part B: r/r HGG Cohort
| DRUG: Topotecan
|
EXPERIMENTAL: Phase I-Part B: r/r MRT Cohort
| DRUG: Topotecan
|
EXPERIMENTAL: Phase I- Part B: r/r RMS Cohort
| DRUG: Topotecan
|
EXPERIMENTAL: Phase II- Ribociclib+Topotecan and Temozolomide
| DRUG: Topotecan
|
PLACEBO_COMPARATOR: Phase II: Placebo+Topotecan and Temozolomide
| DRUG: Topotecan
|
What is the study measuring?
Primary outcome
Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
---|---|---|
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. | Up to 28 days |
Phase I- Part B: Overall response rate (ORR) as assessed by Blinded Independent Review Committee (BIRC) | ORR defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) as assessed by BIRC per: * Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG * International Neuroblastoma Response Criteria (INRC) for participants with NB * Response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with MB, MRT and RMS | Up to 12 months |
Phase II- ORR as assessed by BIRC | ORR defined as the percentage of participants with confirmed best overall response of CR or PR as assessed by BIRC using INRC | Up to 12 months |
Secondary outcome
Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
---|---|---|
Plasma concentrations of ribociclib (Phase I-Part A, Phase I-Part B, Phase II) | 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 | 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, Phase I-Part B, Phase II) | 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 | Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days |
Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A, Phase I-Part B, Phase II) | 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 | 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, Phase I-Part B) | 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. | Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days |
Duration of response (DOR) as assessed by BIRC (Phase I-Part B) | Duration of response is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due any cause. DOR will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B. | Up to 42 months |
Progression Free Survival (PFS) as assessed by BIRC (Phase I-Part B) | PFS is defined as the time from the date of start of treatment to the first documented progression or death due to any cause. PFS will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B. | Up to 42 months |
Time to response (TTR) as assessed by BIRC (Phase I-Part B) | TTR is defined as the time from the date of start of treatment to the first documented progression of either CR or PR. TTR will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B. | Up to 42 months |
Overall survival (Phase I-Part B) | OS is defined as the time from the date of start of treatment to the date of death, due to any cause. OS will be assessed for participants in Phase I-Part B. | Up to 42 months |
Percentage of participants with dose interruptions and dose reductions (Phase I-Part A, Phase I-Part B, Phase II) | Percentage of participants with dose interruptions and dose reductions for participants in Phase I-Part A, Phase I-Part B and Phase II | Up to 12 months |
Duration of response (DOR) as assessed by BIRC (Phase II) | Duration of response is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due any cause. DOR will be assessed by BIRC per RECIST 1.1 for participants in Phase II. | Up to 42 months |
Progression Free Survival (PFS) as assessed by BIRC (Phase II) | PFS is defined as the time from the date of start of treatment to the first documented progression or death due to any cause. PFS will be assessed by BIRC per INRC for participants in Phase II | Up to 42 months |
Time to response (TTR) as assessed by BIRC (Phase II) | TTR is defined as the time from the date of start of treatment to the first documented progression of either CR or PR. TTR will be assessed by BIRC per INRC for participants in Phase II | Up to 42 months |
Clinical benefit rate (CBR) as assessed by BIRC (Phase II) | CBR is defined as the percentage of participants with a best overall response of CR, PR or an overall response of stable disease lasting for a duration of at least 24 weeks. CBR will be assessed by BIRC per INRC for participants in Phase II | Up to 42 months |
Overall survival (OS) (Phase II) | OS is defined as the time from the date of start of treatment to the date of death, due to any cause. OS will be assessed for participants in Phase II | Up to 42 months |
Change from baseline in Pediatric Quality of Life Inventory (PedsQL) questionnaire (Phase II) | PedsQL is a generic instrument used to measure health related quality of life (HRQOL) in children and youth aged 0-25 years. The generic core instrument is available for different age groups and consist of 23 items covering 4 dimensions of HRQOL: Physical functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items) and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale: 0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Items are reverse scored and linearly transformed to a 0-100 scale, where higher scores indicating better QoL. Change from baseline in PedsQL scores will be assessed for participants in Phase II. | Up to 42 months |
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