• Phase I - part A: To determine the MTD and/or 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.

Phase I - Part A: 

1. To characterize the safety and tolerability of ribociclib in combination with TOTEM.
2. To characterize the pharmacokinetics (PK) of ribociclib in combination with TOTEM.

Phase I - Part B:

1. To assess the antitumor activity of ribociclib in combination with TOTEM as assessed by Duration of Response (DOR), Time to Response (TTR), Progression Free Survival (PFS) and Overall Survival (OS).
2. To characterize the safety and tolerability of ribociclib in combination with TOTEM.
3. To characterize the PK of ribociclib in combination with TOTEM.

Phase II:

1.  To assess the treatment effect of ribociclib in combination with TOTEM as assessed by PFS and DOR versus placebo plus TOTEM.
2. To assess the treatment effect of ribociclib in combination with TOTEM as assessed by TTR, Clinical Benefit Rate (CBR), and OS versus placebo plus TOTEM.
3. To characterize the PK of ribociclib in combination with TOTEM.
4. To characterize the safety and tolerability of ribociclib in combination with TOTEM.
5. To describe the effect of ribociclib in combination with TOTEM on Patient Reported Outcomes (PRO).

• Hirntumore
• Kinderonkologie und -hämatologie
• Solide Tumoren

Patients with relapsed or refractory neuroblastoma and other solid tumors

Participants eligible for inclusion in this study must meet all of the following 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. Note: The first cohort of the first dose level of Phase I -  pat A will enroll participants ≥ 12 years - 21 years old. Safety and PK data from these participants will be compared with historical data from clinical trials CLEE011X2102 and CLEE011X2101 to infom the next dose level, and expanding enrollment ot participants aged at ≥ 12 months and ≤ 21 years.

3. Histologically or cytologically confirmed solid tumors listed below that have progressed despite standad therapy or fo which no effective standard therapy exists.

a) Neuroblastoma (Phase I and Phase II)

 i. Histologically proven NB as pe International Neuroblastoma Staging System (INSS).

ii. Relapsed: any relapsed or progressed HR-NB.

iii. Refractory high-risk disease: lack of adequate response to frontline theapy that precludes the participant from peceeding to consolidation therapies (e.g. myeloablative chemotherapy)

iv. Measurable disease by cross sectoinal imaging and/or evaluable disease (uptake on MIBG scan or FDG PET with or without bone marrow histology) pe INRC. Note: Disease need to be assessed and confirmed by BIC fo participants to be enrolled in Phase I - part B and Phase II. Participants with bone marrow disease only are not eligible for this study.

v. Imaging confirmed disease recurrence or progression.

vi. Participants must have an available MYCN amplification status before screeining.

b) Medulloblastoma (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 (Phase I) including (if specified):

i. HGG NOS, Wold Health Oganisation (WHO) grade III o grade IV; 

ii. Glioblastoma, Isocitrate Dehydrogenase (IDH)-wildtype o 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 hemispheic glioma, H3 G34-mutant;

viii. Diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype.

Note: Excluding any low grades (grade I or grade II) such as astrocytoma, oligodendroglioma, or mixed glioneuronal tumors.

 d) Malignant rhabdoid tumor (Phase I) includes diagnoses of atypical teratoid/rhabdoid tumor (AT/RT), and rhabdoid tumo of the kidney (RTK), and other soft tissues as defined by 2 of the 3 following criteria; either (1)+(2) or (1)+(3):

1. Morphology and immunophenotypic panel consistent with rhabdoid tumor 

2. Loss of SMARCB1 confirmed by immunohistochemisty

3. Molecular confirmation of tumor-specific bi-allelic SMARCB1 loss/mutation is encouaged in cases where SMARCB1 immunohistochemistry is equivocal, and required if SMARCB1 immunohistochemistry is not available

 e) Rhabdomyosarcoma (Phase I) independent of fusion status and subtype

4. Participants with Central Nervous System (CNS) disease who are on coticosteroids 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-diected therapy to control their CNS disease are not eligible for the study.

 5. Measurable disease per RANO criteria for participants with HGG and per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 fo MB, MRT, and RMS. Note: Disease need to be assessed and confirmed by BIRC for participants to be enrolled in Phase I - part B.

6. Performance status: Participants who are unable to walk because of paalysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory fo the purpose of assessing performance score

a) ≤ 16 years: Lansky Play score ≥ 50%

b) > 16 years: Karnofsky peformance 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 neuthrophil 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 Upper Limit for Normal (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 based on age/gender normal (Table 5-1). In participants with serum creatinine > 1.5 x ULN for age/gender normal, a calculated glomerular filtration rate (GFR) via 24-hour urine creatinine clearance must be  ≥ 60 milliliter (mL)/min/1.73 m²

g) Adequate cardiac function, defined as corrected QTc interval using Fridericia's correction (QTcF) ≤ 450 milliseconds (ms) and shotening fraction (SF) > 29% (> 35% for children < 3 years) o 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 fo serum albumin)

9. Female participants who are sexually active must agree to use higly effective contraception (Section 8.4.3) during and fo 6 months after treatment. Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prio to the first dose of study medication. Pregnant or lactatin females are not eligible fo the study.

10. Sexually active male participants (including those that have had a vasectomy), who do not agree to abstinence, must be willing to use a condom during intercourse while on study treatment and for 6 months after stopping treatment.

Participants meeting any of the following criteria are not eligible for inclusion in this study

1. Participant has a 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 to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 1, with the exception of alopecia and ototoxicity

3. Concurrent severe and/or uncontrolled medical conditions (serious infections, e.e., COVID-19-related diagnosis, or significant cardiac, pulmonary, hepatic, psychiatic, GI disease, or other organ dysfunction) 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, including any of the following:

a) History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry. 

b) Documented cardiomyopathy

c) Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

i. Risk factor for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cadiac significant/symptomatic bradycardia

ii. Inability to determine the QTcF interval

 d) Clnically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and thid-degree AV block)

5. History of QTcF prolongation (i.e., QTcF interval of > 450 ms) or QTcF < 450 ms on screening Electrocardiogram (ECG).

6. Medicaions with a known risk to prolong the QT interval or induce TdP that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug, whichever is longer).

7. Currently receiving any of the following substances and cannot be discontinued at least 7 days or 5 times reported elimination half-life (whichever is longer) prior to start of treatment with any of the investigational drugs (Cycle 1 Day 1) and for the duration of the study: 

a) Known strong inducers or inhibitors of CYP3A4/5

b) Fruits (grapefruit, grapefruit hybrids, pomelos, star-fruit and Seville oranges) and their juices

c) Herbal preparations/medications and dietary supplements (except for vitamins)

 8. Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrative therapeutic index that cannot be discontinued at least 7 days, or 5 times repoted elimination half-life (whichever is longer) prior to start of treatment with any of the investigation drugs and for the duration of the study. 

9. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.

10. Participated in a prior investigational study (excluding observational studies without treatment) within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.

11. Received prior treatment with CDK4/6 inhibitor.

12. Received last dose of anticance therapy (including experimental) within 4 weeks prior to study enrollment.

13. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose.

14. Allogeneic stem cell transplant within 3 months prior to the first dose. Participants receiving any agent to treat or prevent graft-versus-host-disease (GVHD) post bone marrow transplant are not eligible for this trial.

15. Has had their last fraction of radiation within 4 weeks prior to study enrollment, or within 6 weeks fo therapeutic doses of MIBG, or within 2 weeks prior to enrollment if radiation therapy is given for palliation.

16. Major surgery within 2 weeks from the first dose of ribociclib and not recovered fully from the side effects.