Phase I/II multicenter study to assess 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

INTERVENTION: Product Name: ribociclib Product Code: LEE011 Pharmaceutical Form: Powder for oral solution INN or Proposed INN: Ribociclib CAS Number: 1374639‐75‐4 Current Sponsor code: LEE011 Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 204.082 ‐ Product Name: temozolomide Pharmaceutical Form: Capsule INN or Proposed INN: Temozolomide Other descriptive name: Temozolomide Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ Product Name: topotecan Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: TOPOTECAN HYDROCHLORIDE CAS Number: 119413‐54‐6 Other descriptive name: Topotecan Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Product Name: temozolomide Product Code: L01AX03 Pharmaceutical Form: Capsule INN or Proposed INN: Temozolomide Other descriptive name: Temozolomide Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Product Name: temozolomide Pharmaceutical Form: Capsule INN or Proposed INN: Temozolomide Other descriptive name: Temozolomide Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Product Name: temozolomide Product Code: L01AX03 Pharmaceutical Form: Capsule INN or Proposed INN: Temozolomide Other descriptive name: Temozolomide Concentration type: equal Concentration number: 140‐ Product Name: temozolomide Product Code: L01AX03 Pharmaceutical Form: Capsule INN or Proposed INN: Temozolomide Other descriptive name: Temozolomide Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 250‐ CONDITION: relapsed or refractory neuroblastoma and other solid tumors (including medulloblastoma, high grade glioma, malignant rhabdoid tumors, and rhabdomyosarcoma) in patients from 12 months to 21 years old Therapeutic area: Diseases [C] ‐ Cancer [C04] INCLUSION CRITERIA: 1.Signed informed consent/assent must be obtained prior to participation in the study. Participants and/or guardian must have the ability to understand and the willingness to sign a written informed consent document. 2.Age = 12 months and = 21 years at the time of signing consent form. 3.Histologically or cytologically confirmed solid tumors listed below that have progressed despite standard therapy or for which no effective standard therapy exists. a. Neuroblastoma (NB) (Phase I and Phase II) i. Histologically proven NB as per International Neuroblastoma Staging System (INSS) ii. Relapsed: any relapsed or progressed high‐risk (HR)‐NB iii. Refractory high‐risk disease: lack of adequate response to frontline therapy that precludes the participant from proceeding to consolidation therapies (e.g. myeloblative chemotherapy) iv. Measurable disease by cross sectional imaging and/or evaluable disease (uptake on MIBG scan or FDG PET with or with PRIMARY OUTCOME: Main Objective: Phase I ‐ part A: To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.; Phase I ‐ part B: To evaluate antitumor activity as assessed by Overall Response Rate (ORR) of ribociclib in combination with TOTEM.; Phase II: To evaluate the treatment effect as assessed by ORR of ribociclib in combination with TOTEM versus placebo plus TOTEM.; Primary end point(s): Phase I – part A: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28‐Day cycle); Phase I – part B: ORR (percentage of participants with confirmed best overall of CR or PR) as assessed by Blinded Independent Review Committee (BIRC) per Revised Assessment in Neuro‐Oncology (RANO) criteria for participants with high‐grade glioma (HGG), International Neuroblastoma Response Criteria (INRC) for participants with neuroblastoma (NB), response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with medulloblastoma (MB), malignant rhabdoid tumor (MRT) and rhabdomyosarcoma (RMS); Phase II: ORR (percentage of participants with confirmed best overall confirmed CR or PR) as assessed by BIRC using INRC; Secondary Objective: Phase I – part A: ; • to characterize the safety and tolerability of ribociclib in combination with TOTEM (ribociclib+TOTEM); • to characterize the pharmacokinetics (PK) of ribociclib+TOTEM; Phase I – part B: ; • to assess the antitumor activity of ribociclib+TOTEM as assessed by Duration of response (DOR), PFS, Time to response (TTR), and OS.; • to characterize the safety and tolerability of ribociclib+TOTEM; • to characterize the PK of ribociclib+TOTEM; Phase II: ; • to assess the treatment effect of ribociclib+TOTEM as assessed by PFS and DOR versus placebo plus TOTEM.; • to assess the treatment effect of ribociclib+TOTEM as assessed by TTR, Clinical Benefit Rate, and OS versus placebo plus TOTEM.; • to characterize the PK of ribociclib+TOTEM.; • to characterize the safety and tolerability of ribociclib+TOTEM.; • to describe the effect of ribociclib+TOTEM on Patient Reported Outcomes (PRO).; ; Timepoint(s) of evaluation of this end point: Phase I – part A: 9 months from trial start until declaring MTD/RP2D; Phase I – part B: 15 months from the Phase IB trial start till completion of Phase IB; Phase II: 40 months from the Phase II trial randomization till completion of Phase II (including 6 months from the last patient enrolled); SECONDARY OUTCOME: Secondary end point(s): Phase I – part A:; • Safety: Incidence, type, and severity of adverse events (AEs) per common terminology criteria for adverse events (CTCAE) version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments, and incidence of DLTs in Cycle 1.; Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.; • Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.; Phase I – part B:; • DOR, PFS, TTR per RANO criteria for participants with HGG, INRC for participants with NB, RECIST 1.1 for participants with MB, MRT and RMS as assessed by BIRC assessment, and OS.; • Safety: Incidence, type, and severity of AEs per CTCAE version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments and incidence of DLTs in Cycle 1.; Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.; • Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.; Phase II:; • PFS and DOR using INRC as assessed by BIRC (key secondary endpoints).; • TTR, CBR using INRC as assessed by BIRC and OS.; • Plasma concentrations of ribociclib, topotecan, temozolomide and derived PK parameters of ribociclib such as AUC and Cmax.; • Safety: Incidence, type, and severity of adverse events per CTCAE version 5.0 criteria including changes in laboratory values, performance status, vital signs, liver assessments and cardiac assessments.; Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.; • PRO as measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire.; Timepoint(s) of evaluation of this end point: Phase I – part A: 9 months from trial start until declaring MTD/RP2D; Phase I – part B: 15 months from the Phase IB trial start till completion of Phase IB; Phase II: 40 months from the Phase II trial randomization till completion of Phase II (including 6 months from the last patient enrolled);