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

NCT05429502 | Terminated Phase 1 FDA Drug

• 2 other identifiers: CLEE011Q121012024-512095-35-00
• Study Type: interventional
• Target: 12
• Locations: 4 countries
• Sites: 6

Brief Summary

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).

Conditions

Neuroblastoma

Keywords

neuroblastoma; medulloblastoma; high-grade glioma; malignant rhabdoid tumors; rhabdomyosarcoma; relapsed; refractory; pediatric

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (5)

• Plasma concentrations of ribociclib (Phase I-Part A)

  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)

  Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days

• Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A)

  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)

  Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days

• Percentage of participants with dose interruptions and dose reductions (Phase I-Part A)

  Up to 12 months

Study Arms (1)

Phase I-part A: Ribociclib + Topotecan and Temozolomide

EXPERIMENTAL

Participants with r/r NB, MB, HGG, MRT or RMS will be treated with ribociclib in combination with topotecan and temozolomide to determine MTD and/or RP2D. Ribociclib dose will be escalated with topotecan and temozolomide.

Drug: Topotecan; Drug: Temozolomide; Drug: Ribociclib

Interventions

Topotecan DRUG

Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).

Also known as: Hycamtin

Phase I-part A: Ribociclib + Topotecan and Temozolomide

Temozolomide DRUG

Starting out dose of temozolomide for cohort A1 and A2 for Phase 1-Part A: 150mg/m2/day. Starting out dose for subsequent cohorts, Cohort A3 and onwards, in Phase 1-Part A will initiate at 100mg/m2/day.

Also known as: Temodar

Phase I-part A: Ribociclib + Topotecan and Temozolomide

Ribociclib DRUG

Starting out dose of ribociclib for cohort A1 Phase 1-Part A: 200mg/m2/day. Starting out dose for Cohort A2 and A3 was 100mg/m2/day.

Also known as: Kisqali, LEE011

Phase I-part A: Ribociclib + Topotecan and Temozolomide

Eligibility Criteria

• Age: 12 Months - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document.
• Age ≥ 12 months and ≤ 21 years at the time of signing consent form Note: The first dose level of Phase I - part A (dose finding) will enroll participants ≥ 12 years - 21 years old, and may expand to younger participants (≥ 12 months to \< 12 years) as determined by the data.
• Histologically or cytologically confirmed solid tumors listed below that have progressed despite standard therapy or for which no effective standard therapy exists.
• Neuroblastoma (for Phase I and Phase II): Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS); Relapsed or refractory disease; Measurable disease per International Neuroblastoma Response criteria (INRC); Bone marrow only disease not eligible; Available MYCN status before screening
• Medulloblastoma (for Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH)
• High-grade glioma (for Phase I): including HGG NOS, WHO Grade III or Grade IV; Glioblastoma, IDH-wildtype or IDH-mutant; Anaplastic astrocytoma, IDH-mutant; Anaplastic oligodendroglioma, IDH-mutant; Anaplastic pleomorphic xanthoastrocytoma; Diffuse midline gliomas, H3 K27-altered; Diffuse hemispheric glioma, H3 G34-mutant; Diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype.
• Malignant rhabdoid tumor (for 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 (1)+(2) or (1)+(3): (1) Morphology and immunophenotypic panel consistent with rhabdoid tumor; (2) Loss of SMARCB1 confirmed by immunohistochemistry; (3) 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
• Rhabdomyosarcoma (for Phase I) independent of fusion status and subtype
• Participants with 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.
• Performance status:
• ≤ 16 years: Lansky Play score ≥ 50%
• \>16 years: Karnofsky performance status ≥ 50% or ECOG \< 3
• Life expectancy of ≥ 12 weeks at the time of enrollment
• Adequate bone marrow function (bone marrow may be involved with tumor) and organ function
• Adequate hepatic, renal, cardiac function

You may not qualify if:

• Known hypersensitivity to any of the excipients of ribociclib or topotecan or temozolomide.
• Not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies
• Concurrent severe and/or uncontrolled concurrent medical conditions (serious infections or significant cardiac, pulmonary, hepatic, psychiatric, 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
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality
• History of QTc prolongation; taking medications with a known risk to prolong the QT interval hat cannot be discontinued or replaced by safe alternative medication
• Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrow therapeutic index, strong inducers or inhibitors of CYP3A4/5, herbal preparations/medications and dietary supplements
• Vaccinated with live, attenuated vaccines within 4 weeks
• Participated in a prior investigational study within 30 days
• Received prior treatment with a CDK4/6 inhibitor
• Received last dose of anticancer therapy (including experimental) within 4 weeks
• Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks
• Allogeneic stem cell transplant within 3 months
• Has last fraction of radiation within 4 weeks
• Major surgery within 2 weeks
• Pregnant or nursing (breast feeding) female participant or female participant who plans to become pregnant or breast-feed during the trial.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Innovative Therapies For Children with Cancer Consortium: collaborator

Study Sites (6)

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Cohen Children's Medical Center of New York

New Hyde Park, New York, 11040, United States

Location

St Jude s Childrens Research Hospital

Memphis, Tennessee, 38105-2794, United States

Location

Novartis Investigative Site

Cologne, 50937, Germany

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Links

• Link to study results
• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Neuroblastoma; Medulloblastoma; Glioma; Rhabdomyosarcoma; Recurrence

Interventions

Topotecan; Temozolomide; ribociclib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Myosarcoma; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Cohort A1 - concurrent regimen Cohort A2 - sequential regimen Cohort A3 (post protocol amendment #2) - concurrent

Study Record Dates

• First Submitted: June 17, 2022
• First Posted: June 23, 2022
• Study Start: December 27, 2022
• Primary Completion: February 26, 2025
• Study Completion: February 26, 2025
• Last Updated: October 10, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); DE (1); US (3); GB (1)