Study to assess safety and identify dose of ribociclib in combination of temozolomide and topotecan (TOTEM) in patients (12 months – 21 years old) with relapsed or refractory solid tumors (Phase I), and further assess efficacy and safety in patients (12 months – 21 years old) with relapsed or refractory neuroblastoma (Phase II)
- Conditions
- 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 oldMedDRA version: 20.0Level: PTClassification code 10029260Term: NeuroblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: LLTClassification code 10029261Term: Neuroblastoma NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-005617-14-DK
- Lead Sponsor
- ovartis Pharma AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 230
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 funct
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 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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method