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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

Study Purpose

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).

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 12 Months - 21 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. Participants and/or guardian 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 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.
3. Histologically or cytologically confirmed solid tumors listed below that have progressed despite standard therapy or for which no effective standard therapy exists. 1. 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. 2. Medulloblastoma (for Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH) 3. 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. 4. 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.
5. Rhabdomyosarcoma (for Phase I) independent of fusion status and subtype. 4. 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. 5. Performance status: 1. ≤ 16 years: Lansky Play score ≥ 50% 2. >16 years: Karnofsky performance status ≥ 50% or ECOG < 3. 6. Life expectancy of ≥ 12 weeks at the time of enrollment. 7. Adequate bone marrow function (bone marrow may be involved with tumor) and organ function. 8. Adequate hepatic, renal, cardiac function. 9. Females who are sexually active must agree to use highly effective contraception during and for 6 months after treatment. Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study medication. Pregnant or lactating females are not eligible for the study. 10. Sexually active males (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.

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 (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. 4. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. 5. 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. 6. 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. 7. Vaccinated with live, attenuated vaccines within 4 weeks. 8. Participated in a prior investigational study within 30 days. 9. Received prior treatment with a CDK4/6 inhibitor. 10. Received last dose of anticancer therapy (including experimental) within 4 weeks. 11. Previous myeloblative therapy with autologous hematopoietic stem cell rescue within 8 weeks. 12. Allogeneic stem cell transplant within 3 months. 13. Has last fraction of radiation within 4 weeks. 14. Major surgery within 2 weeks. Other protocol-defined inclusion/exclusion criteria may apply

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT05429502
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Novartis Pharmaceuticals
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Novartis Pharmaceuticals
Principal Investigator Affiliation Novartis Pharmaceuticals
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Industry, Other
Overall Status Recruiting
Countries Australia, France, Germany, Italy, Singapore, Spain, United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Neuroblastoma
Additional Details

The study consists of Phase I -part A (dose finding) and Phase I

  • - part B (multiple expansion cohorts).
Phase II may begin after evaluation of Phase I data (safety, tolerability, efficacy, pharmacokinetics and biomarker data), with consideration of other emerging data that may impact on the treatment landscape, before initiating Phase II in patients with relapsed or refractory NB and/or other tumors studied in Phase
  • I. - Phase I-Part A (dose finding): a dose finding to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.
  • - Phase I- Part B (multiple expansion cohorts): it will be initiated to confirm RP2D identified from Phase I-part A.
Multiple expansion cohorts have been planned to assess the preliminary antitumor activity and safety of ribociclib in combination with TOTEM in participants with r/r NB (cohort 1), MB (cohort 2), HGG (cohort 3), MRT (cohort 4), and RMS (cohort 5)
  • - Phase II- Double-blind, randomized, placebo controlled in r/r NB: It is a two-arm randomized, double blinded, placebo controlled, parallel group trial in participants with r/r NB.

Arms & Interventions

Arms

Experimental: Phase I-part A: Ribociclib+TOTEM

Participants with r/r NB, MB, HGG, MRT or RMS will be treated with ribociclib in combination with TOTEM to determine MTD and/or RP2D. Ribociclib dose will be scalated while topotecan and temozolomide will be administered at a fixed dose.

Experimental: Phase I- Part B: r/r NB Cohort

Participants with r/r NB will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A

Experimental: Phase I- Part B: r/r MB Cohort

Participants with r/r MB will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A

Experimental: Phase I-Part B: r/r HGG Cohort

Participants with r/r HGG will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A

Experimental: Phase I-Part B: r/r MRT Cohort

Participants with r/r MRT will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A

Experimental: Phase I- Part B: r/r RMS Cohort

Participants with r/r RMS will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A

Experimental: Phase II- Ribociclib+TOTEM

Participants with r/r NB will be treated with ribocilib in combination with TOTEM at the RP2D defined from Phase I part A.

Placebo Comparator: Phase II: Placebo+TOTEM

Participants with r/r NB will be treated ribociclib matching placebo in combination with TOTEM

Interventions

Drug: - Topotecan

Topotecan administered at the standard dose given to neuroblastoma patients

Drug: - Temozolomide

Temozolamide administered at the standard dose given to neuroblastoma patients

Drug: - Ribociclib

Ribociclib administered at the RP2D defined from Phase I-Part A.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Dana Farber Cancer Institute ., Boston, Massachusetts

Status

Recruiting

Address

Dana Farber Cancer Institute .

Boston, Massachusetts, 02115

Site Contact

Jessica Fernandes

[email protected]

617-632-5136

Memphis, Tennessee

Status

Recruiting

Address

St Jude s Childrens Research Hospital Dept of Regulatory

Memphis, Tennessee, 38105-2794

Site Contact

Dana Hawkins

[email protected]

901-595-5597

International Sites

Novartis Investigative Site, Randwick, New South Wales, Australia

Status

Recruiting

Address

Novartis Investigative Site

Randwick, New South Wales, 2130

Novartis Investigative Site, Villejuif, France

Status

Recruiting

Address

Novartis Investigative Site

Villejuif, , 94800

Novartis Investigative Site, Koeln, Germany

Status

Recruiting

Address

Novartis Investigative Site

Koeln, , 50937

Novartis Investigative Site, Milano, MI, Italy

Status

Recruiting

Address

Novartis Investigative Site

Milano, MI, 20133

Novartis Investigative Site, Singapore, Singapore

Status

Recruiting

Address

Novartis Investigative Site

Singapore, , 119074

Novartis Investigative Site, Singapore, Singapore

Status

Recruiting

Address

Novartis Investigative Site

Singapore, , 229899

Novartis Investigative Site, Barcelona, Catalunya, Spain

Status

Recruiting

Address

Novartis Investigative Site

Barcelona, Catalunya, 08035