| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
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| E.1.1.1 | Medical condition in easily understood language |
| Recurrent solid tumors in patients from 12 months to 21 years old |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
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).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 without bone marrow histology) per International Neuroblastoma Response Criteria (INRC).
v. Imaging confirmed disease recurrence or progression
vi. Participants must have an available MYCN amplification status before screening.
b. Medulloblastoma (MB) (Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH).
c. High-grade glioma (HGG) (Phase I): Note: excluding any low grades (grade I or grade II) such as astrocytoma, oligodendroglioma, or mixed glioneuronal tumors
i. HGG, not otherwise specified (NOS), WHO Grade III or Grade IV
ii. Glioblastoma, IDH-wildtype, or IDH-mutant
iii. Anaplastic astrocytoma, IDH mutant
iv. Anaplastic oligodendroglioma, IDH mutant
v. Anaplastic pleomorphic xanthoastrocytoma
vi. Diffuse midline gliomas, H3 K27-altered
vii. Diffuse hemispheric glioma, H3 G34-mutant
viii. Diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype
d. Malignant rhabdoid tumor (MRT) (Phase I): includes diagnoses of atypical teratoid/rhabdoid tumor (AT/RT), and rhabdoid tumor of the kidney (RTK), and other soft tissues as defined by 2 of the 3 following criteria; either (i)+(ii) or (i)+(iii):
i. Morphology and immunophenotypic panel consistent with rhabdoid tumor
ii. Loss of SMARCB1 confirmed by immunohistochemistry
iii. Molecular confirmation of tumor-specific bi-allelic SMARCB1 loss/mutation is encouraged in cases where SMARCB1 immunohistochemistry is equivocal and required if SMARCB1 immunohistochemistry is not available.
e. Rhabdomyosarcoma (RMS) (Phase I) independent of fusion status and subtype.
4.Participants with central nervous system (CNS) disease who are on corticosteroids should take stable doses for at least 7 days prior to first dose of ribociclib with no plans for escalation. Note: participants with symptomatic CNS disease who are neurologically unstable or require local CNS-directed therapy to control their CNS disease are not eligible for the study.
5.Measurable disease per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for MB, MRT and RMS.
6.Performance status: participants who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score
a.≤ 16 years: Lansky Play score ≥ 50%
b.>16 years: Karnofsky performance status ≥ 50% or ECOG < 3
7.Life expectancy of ≥ 12 weeks at the time of enrollment.
8.Adequate bone marrow function (bone marrow may be involved with tumor) and organ function defined as:
a. Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 without growth factor support within 7 days of the test
b. Platelet count ≥ 75,000/mm3 without support within 7 days of the test
c. Hemoglobin ≥ 8.0 g/dL (transfusion allowed)
d. Total bilirubin ≤ 1.5 x ULN for age (in case of Gilbert’s syndrome, ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN for age)
e. Adequate liver function, defined as total serum bilirubin ≤ 1.5 x ULN AND alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤ 2.5 x ULN (in case of liver metastases, AST / ALT ≤ 5 x ULN)
f. Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN based on age/gender normal. In participants with serum creatinine > 1.5 x ULN for age/gender normal, a calculated glomerular filtration rate (GFR) must be ≥ 60 mL/min/1.73 m2.
g. Adequate cardiac function, defined as corrected QTc interval using Fridericia’s correction (QTcF) ≤ 450 ms and shortening fraction (SF) > 29% (> 35% for participants < 3 years) or left ventricular ejection fraction (LVEF) ≥ 50% on echocardiogram
h. The following laboratory values within normal limits or corrected to within normal limits with supplements before first dose of study medication:
i. Potassium
ii. Magnesium
iii. Total calcium (corrected for serum albumin)
- Other protocol-defined inclusion criteria may apply |
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| E.4 | Principal exclusion criteria |
1. Known hypersensitivity to any of the excipients of ribociclib or topotecan or temozolomide.
2. Not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies.
3. Concurrent severe and/or uncontrolled concurrent medical conditions that in the Investigator's judgement could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results.
4. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
5. History of QTcF prolongation (i.e. QTcF interval of > 450 ms) or QTcF > 450 ms on screening ECG.
6. Currently taking medications with a known risk to prolong the QT interval or induce TdP that cannot be discontinued or replaced by safe alternative medication.
7. Currently taking medications that are known strong inducers or inhibitors of CYP3A4/5 cannot be discontinued at least 7 days or 5 half-lives.
8. Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrow therapeutic index that cannot be discontinued at least 7 days or 5 half-lives.
9. Vaccinated with live, attenuated vaccines within 4 weeks.
10. Participated in a investigational study (excluding observational studies without treatment)within 30 days or 5 half-lives.
11. Received prior treatment with a CDK4/6 inhibitor.
12. Received anticancer therapy (including experimental) within 4 weeks.
13. Received myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks.
14. Received allogeneic stem cell transplant within 3 months.
15. Has radiation within 4 weeks (or 2 weeks if radiation therapy is given for palliation), or within 6 weeks of MIBG treatment.
16. Major surgery within 2 weeks and not recovered fully from the side effects.
- Other protocol-defined exclusion criteria may apply |
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| E.5 End points |
| E.5.1 | 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
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| E.5.1.1 | 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)
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| E.5.2 | 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.
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| E.5.2.1 | 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)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Acceptability, palatability, PRO |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I/II in new population and indication |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Australia |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Study completion is defined as when the last patient finishes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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