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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

PHASE1PHASE2RECRUITING

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).

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Study 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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

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.

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

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.

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

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 myeloblative 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.

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Eligibility

Age eligible for study : 12 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-12-27

Primary completion: 2029-02-28

Study completion finish: 2029-02-28

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT05429502

Intervention or treatment

DRUG: Topotecan

DRUG: Temozolomide

DRUG: Ribociclib

Conditions

• Neuroblastoma

Condition: Neuroblastoma
DRUG: Topotecan and other drugs
Randwick, New South Wales, Australia
Sponsor: Novartis Pharmaceuticals

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Find a site

Closest Location:

Novartis Investigative Site

Research sites nearby

Select from list below to view details:

Novartis Investigative Site
Randwick, New South Wales, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
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.	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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.	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).
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	DRUG: Topotecan Starting out dose of topotecan administered at standard dose given to neuroblastoma patients (0.75 mg/m2/day).

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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
Phase I- Part B: Overall response rate (ORR) as assessed by Blinded Independent Review Committee (BIRC)	ORR defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) as assessed by BIRC per: * Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG * International Neuroblastoma Response Criteria (INRC) for participants with NB * Response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with MB, MRT and RMS	Up to 12 months
Phase II- ORR as assessed by BIRC	ORR defined as the percentage of participants with confirmed best overall response of CR or PR as assessed by BIRC using INRC	Up to 12 months

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Plasma concentrations of ribociclib (Phase I-Part A, Phase I-Part B, Phase II)	Pharmacokinetic (PK) blood samples will be collected at selected time-points to determine ribociclib plasma concentrations from participants in Phase I-Part A, Phase I-Part B and Phase II	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, Phase I-Part B, Phase II)	PK blood samples will be collected at selected time-points to determine AUC of ribociclib from participants in Phase I-Part A, Phase I-Part B and Phase II	Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A, Phase I-Part B, Phase II)	PK blood samples will be collected at selected time-points to determine Cmax of ribociclib from participants in Phase I-Part A, Phase I-Part B and Phase II	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, Phase I-Part B)	PK blood samples will be collected at selected time-points to determine Cmax of ribociclib from participants in Phase I-Part A and Phase I-Part B.	Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days
Duration of response (DOR) as assessed by BIRC (Phase I-Part B)	Duration of response is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due any cause. DOR will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B.	Up to 42 months
Progression Free Survival (PFS) as assessed by BIRC (Phase I-Part B)	PFS is defined as the time from the date of start of treatment to the first documented progression or death due to any cause. PFS will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B.	Up to 42 months
Time to response (TTR) as assessed by BIRC (Phase I-Part B)	TTR is defined as the time from the date of start of treatment to the first documented progression of either CR or PR. TTR will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B.	Up to 42 months
Overall survival (Phase I-Part B)	OS is defined as the time from the date of start of treatment to the date of death, due to any cause. OS will be assessed for participants in Phase I-Part B.	Up to 42 months
Percentage of participants with dose interruptions and dose reductions (Phase I-Part A, Phase I-Part B, Phase II)	Percentage of participants with dose interruptions and dose reductions for participants in Phase I-Part A, Phase I-Part B and Phase II	Up to 12 months
Duration of response (DOR) as assessed by BIRC (Phase II)	Duration of response is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due any cause. DOR will be assessed by BIRC per RECIST 1.1 for participants in Phase II.	Up to 42 months
Progression Free Survival (PFS) as assessed by BIRC (Phase II)	PFS is defined as the time from the date of start of treatment to the first documented progression or death due to any cause. PFS will be assessed by BIRC per INRC for participants in Phase II	Up to 42 months
Time to response (TTR) as assessed by BIRC (Phase II)	TTR is defined as the time from the date of start of treatment to the first documented progression of either CR or PR. TTR will be assessed by BIRC per INRC for participants in Phase II	Up to 42 months
Clinical benefit rate (CBR) as assessed by BIRC (Phase II)	CBR is defined as the percentage of participants with a best overall response of CR, PR or an overall response of stable disease lasting for a duration of at least 24 weeks. CBR will be assessed by BIRC per INRC for participants in Phase II	Up to 42 months
Overall survival (OS) (Phase II)	OS is defined as the time from the date of start of treatment to the date of death, due to any cause. OS will be assessed for participants in Phase II	Up to 42 months
Change from baseline in Pediatric Quality of Life Inventory (PedsQL) questionnaire (Phase II)	PedsQL is a generic instrument used to measure health related quality of life (HRQOL) in children and youth aged 0-25 years. The generic core instrument is available for different age groups and consist of 23 items covering 4 dimensions of HRQOL: Physical functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items) and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale: 0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Items are reverse scored and linearly transformed to a 0-100 scale, where higher scores indicating better QoL. Change from baseline in PedsQL scores will be assessed for participants in Phase II.	Up to 42 months

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References

Clinical Trials Gov: 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