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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Dec 2022 → 26 Feb 2025

Decision date (initial)

2024-04-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2024-512095-35-00

EudraCT number

2021-005617-14

ClinicalTrials.gov

NCT05429502

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Dose response, Efficacy, Pharmacokinetic, Pharmacodynamic, Safety

Phase I - part A:
To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.
Phase I - part B:
To evaluate antitumor activity as assessed by Overall Response Rate (ORR) of ribociclib in combination with TOTEM.
Phase II: To evaluate the treatment effect as assessed by ORR of ribociclib in combination with TOTEM versus placebo plus TOTEM.

Secondary objectives 3

1. Phase I – part A: • to characterize the safety and tolerability of ribociclib in combination with TOTEM (ribociclib+TOTEM) • to characterize the pharmacokinetics (PK) of ribociclib+TOTEM
2. Phase I – part B: • to assess the antitumor activity of ribociclib+TOTEM as assessed by Duration of response (DOR), PFS, Time to response (TTR), and OS. • to characterize the safety and tolerability of ribociclib+TOTEM • to characterize the PK of ribociclib+TOTEM
3. Phase II: • to assess the treatment effect of ribociclib+TOTEM as assessed by PFS and DOR versus placebo plus TOTEM. • to assess the treatment effect of ribociclib+TOTEM as assessed by TTR, Clinical Benefit Rate, and OS versus placebo plus TOTEM. • to characterize the PK of ribociclib+TOTEM. • to characterize the safety and tolerability of ribociclib+TOTEM. • to describe the effect of ribociclib+TOTEM on Patient Reported Outcomes (PRO).

Conditions and MedDRA coding

Relapsed or refractory neuroblastoma and other solid tumors (including medulloblastoma, high grade glioma, malignant rhabdoid tumors, and rhabdomyosarcoma)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002765-PIP02-21

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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) 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 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): 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
7. Life expectancy of ≥ 12 weeks at the time of enrollment.
8. Adequate bone marrow function (bone marrow may be involved with tumor) and organ function defined as: a. Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 without growth factor support within 7 days of the test b. Platelet count ≥ 75,000/mm3 without support within 7 days of the test c. Hemoglobin ≥ 8.0 g/dL (transfusion allowed) d. Total bilirubin ≤ 1.5 x ULN for age (in case of Gilbert's syndrome, ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN for age) e. Adequate liver function, defined as total serum bilirubin ≤ 1.5 x ULN AND alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤ 2.5 x ULN (in case of liver metastases, AST / ALT ≤ 5 x ULN) f. Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN based on age/gender normal. In participants with serum creatinine > 1.5 x ULN for age/gender normal, a calculated glomerular filtration rate (GFR) must be ≥ 60 mL/min/1.73 m2. g. Adequate cardiac function, defined as corrected QTc interval using Fridericia's correction (QTcF) ≤ 450 ms and shortening fraction (SF) > 29% (> 35% for participants < 3 years) and left ventricular ejection fraction (LVEF) ≥ 50% on echocardiogram h. The following laboratory values within normal limits or corrected to within normal limits with supplements before first dose of study medication: Potassium; Magnesium; Total calcium (corrected for serum albumin)

Exclusion criteria 16

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 halflives
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phase I – part A: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28-Day cycle)
2. Phase I – part B: ORR (percentage of participants with confirmed best overall of CR or PR) as assessed by Blinded Independent Review Committee (BIRC) per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with high-grade glioma (HGG), International Neuroblastoma Response Criteria (INRC) for participants with neuroblastoma (NB), response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with medulloblastoma, malignant rhabdoid tumor and rhabdomyosarcoma
3. Phase II: ORR (percentage of participants with confirmed best overall confirmed CR or PR) as assessed by BIRC using INRC

Secondary endpoints 9

1. Phase I – part A: Safety: Incidence, type, and severity of adverse events (AEs) per common terminology criteria for adverse events (CTCAE) version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments, and incidence of DLTs in Cycle 1. Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
2. Phase I – part A: Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
3. Phase I – part B: DOR, PFS, TTR per RANO criteria for participants with HGG, INRC for participants with NB, RECIST 1.1 for participants with MB, MRT and RMS as assessed by BIRC assessment, and OS.
4. Phase I – part B: Safety: Incidence, type, and severity of AEs per CTCAE version 5.0 including changes in laboratory values, performance status, vital signs, liver assessments, cardiac assessments and incidence of DLTs in Cycle 1. Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
5. Phase I – part B: Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
6. Phase II: PFS and DOR using INRC as assessed by BIRC (key secondary endpoints). TTR, CBR using INRC as assessed by BIRC and OS
7. Phase II: Plasma concentrations of ribociclib, topotecan, temozolomide and derived PK parameters of ribociclib such as AUC and Cmax.
8. Phase II: Safety: Incidence, type, and severity of adverse events per CTCAE version 5.0 criteria including changes in laboratory values, performance status, vital signs, liver assessments and cardiac assessments. Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components.
9. Phase II: PRO as measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 13

Locations

7 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications