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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05429502




Registration number
NCT05429502
Ethics application status
Date submitted
17/06/2022
Date registered
23/06/2022
Date last updated
13/05/2024

Titles & IDs
Public title
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
Scientific title
Phase I/II Multicenter Study to Assess 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
Secondary ID [1] 0 0
2021-005617-14
Secondary ID [2] 0 0
CLEE011Q12101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuroblastoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Topotecan
Treatment: Drugs - Temozolomide
Treatment: Drugs - Ribociclib

Experimental: Phase I-part A: Ribociclib + Topotecan and Temozolomide - 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.

Experimental: Phase I- Part B: r/r NB Cohort - Participants with r/r NB will be treated with ribociclib in combination with topotecan and temozolomide 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 topotecan and temozolomide 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 topotecan and temozolomide 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 topotecan and temozolomide 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 topotecan and temozolomide at the PR2D identified from Phase I-Part A

Experimental: Phase II- Ribociclib+Topotecan and Temozolomide - Participants with r/r NB will be treated with ribocilib in combination with topotecan and temozolomide at the RP2D defined from Phase I part A.

Placebo Comparator: Phase II: Placebo+Topotecan and Temozolomide - Participants with r/r NB will be treated ribociclib matching placebo in combination with topotecan and temozolomide


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

Treatment: Drugs: Temozolomide
Starting out dose of temozolomide for first two cohorts for Phase 1-Part A: 150mg/m2/day. Starting out dose for subsequent cohorts in Phase 1-Part A will initiate at 100mg/m2/day and will be determined for Phase 1-Part B depending on safety outcome and for phase II.

Treatment: Drugs: Ribociclib
Ribociclib administered at the RP2D defined from Phase I-Part A.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1- Part A: Percentage of participants with Dose Limiting Toxicities (DLTs) in Cycle 1
Timepoint [1] 0 0
Up to 28 days
Primary outcome [2] 0 0
Phase I- Part B: Overall response rate (ORR) as assessed by Blinded Independent Review Committee (BIRC)
Timepoint [2] 0 0
Up to 12 months
Primary outcome [3] 0 0
Phase II- ORR as assessed by BIRC
Timepoint [3] 0 0
Up to 12 months
Secondary outcome [1] 0 0
Plasma concentrations of ribociclib (Phase I-Part A, Phase I-Part B, Phase II)
Timepoint [1] 0 0
Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Secondary outcome [2] 0 0
Area under the plasma concentration-time curve (AUC) of ribociclib (Phase I-Part A, Phase I-Part B, Phase II)
Timepoint [2] 0 0
Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Secondary outcome [3] 0 0
Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A, Phase I-Part B, Phase II)
Timepoint [3] 0 0
Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Secondary outcome [4] 0 0
Time of maximum plasma concentration (Tmax) of ribociclib (Phase I-Part A, Phase I-Part B)
Timepoint [4] 0 0
Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Secondary outcome [5] 0 0
Duration of response (DOR) as assessed by BIRC (Phase I-Part B)
Timepoint [5] 0 0
Up to 42 months
Secondary outcome [6] 0 0
Progression Free Survival (PFS) as assessed by BIRC (Phase I-Part B)
Timepoint [6] 0 0
Up to 42 months
Secondary outcome [7] 0 0
Time to response (TTR) as assessed by BIRC (Phase I-Part B)
Timepoint [7] 0 0
Up to 42 months
Secondary outcome [8] 0 0
Overall survival (Phase I-Part B)
Timepoint [8] 0 0
Up to 42 months
Secondary outcome [9] 0 0
Percentage of participants with dose interruptions and dose reductions (Phase I-Part A, Phase I-Part B, Phase II)
Timepoint [9] 0 0
Up to 12 months
Secondary outcome [10] 0 0
Duration of response (DOR) as assessed by BIRC (Phase II)
Timepoint [10] 0 0
Up to 42 months
Secondary outcome [11] 0 0
Progression Free Survival (PFS) as assessed by BIRC (Phase II)
Timepoint [11] 0 0
Up to 42 months
Secondary outcome [12] 0 0
Time to response (TTR) as assessed by BIRC (Phase II)
Timepoint [12] 0 0
Up to 42 months
Secondary outcome [13] 0 0
Clinical benefit rate (CBR) as assessed by BIRC (Phase II)
Timepoint [13] 0 0
Up to 42 months
Secondary outcome [14] 0 0
Overall survival (OS) (Phase II)
Timepoint [14] 0 0
Up to 42 months
Secondary outcome [15] 0 0
Change from baseline in Pediatric Quality of Life Inventory (PedsQL) questionnaire (Phase II)
Timepoint [15] 0 0
Up to 42 months

Eligibility
Key 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.
Minimum age
12 Months
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

15. Pregnant or nursing (breast feeding) female participant or female participant who
plans to become pregnant or breast-feed during the trial.

Other protocol-defined inclusion/exclusion criteria may apply

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
27/12/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
29/01/2029
Actual
Sample size
Target
231
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Novartis Investigative Site - Randwick
Recruitment postcode(s) [1] 0 0
2130 - Randwick
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
United States of America
State/province [2] 0 0
Tennessee
Country [3] 0 0
France
State/province [3] 0 0
Villejuif
Country [4] 0 0
Germany
State/province [4] 0 0
Koeln
Country [5] 0 0
Italy
State/province [5] 0 0
MI
Country [6] 0 0
Singapore
State/province [6] 0 0
Singapore
Country [7] 0 0
Spain
State/province [7] 0 0
Catalunya

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Innovative Therapies For Children with Cancer Consortium
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/ct2/show/NCT05429502
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Country 0 0
Phone 0 0
1-888-669-6682
Fax 0 0
Email 0 0
novartis.email@novartis.com
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05429502