2024-512095-35-00
Completed
Phase 1/2
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
Overview
- Phase
- Phase 1/2
- Status
- Completed
- Sponsor
- Novartis Pharma AG
- Enrollment
- 49
- Locations
- 18
- Primary Endpoint
- 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
Overview
Brief Summary
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.
Eligibility Criteria
- Ages
- 0 years to 64 years (0-17 Years, 18-64 Years)
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •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.
- •Age ≥ 12 months and ≤ 21 years at the time of signing consent form.
- •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.
- •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
- •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.
- •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
- •Life expectancy of ≥ 12 weeks at the time of enrollment.
- •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 m
- •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
- •Known hypersensitivity to any of the excipients of ribociclib or topotecan or temozolomide.
- •Participated in a investigational study within 30 days or 5 half-lives
- •Received prior treatment with a CDK4/6 inhibitor
- •Received anticancer therapy (including experimental) within 4 weeks
- •Received myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks
- •Received allogeneic stem cell transplant within 3 months
- •Has radiation within 4 weeks (or 2 weeks if radiation therapy is given for palliation), or within 6 weeks of MIBG treatment
- •Major surgery within 2 weeks and not recovered fully from the side effects
- •Not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies
- •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
Outcomes
Primary Outcomes
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
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
Phase II: ORR (percentage of participants with confirmed best overall confirmed CR or PR) as assessed by BIRC using INRC
Phase II: ORR (percentage of participants with confirmed best overall confirmed CR or PR) as assessed by BIRC using INRC
Phase I – part A: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28-Day cycle)
Phase I – part A: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28-Day cycle)
Secondary Outcomes
- 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.
- Phase I – part A: Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
- 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.
- 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.
- Phase I – part B: Plasma concentrations of ribociclib and derived PK parameters such as AUC, Cmax, Tmax.
- Phase II: PFS and DOR using INRC as assessed by BIRC (key secondary endpoints). TTR, CBR using INRC as assessed by BIRC and OS
- Phase II: Plasma concentrations of ribociclib, topotecan, temozolomide and derived PK parameters of ribociclib such as AUC and Cmax.
- 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.
- Phase II: PRO as measured by the Pediatric Quality of Life Inventory (PedsQL) questionnaire.
Investigators
Novartis Pharma Arzneimittel GmbH
Scientific
Novartis Pharma AG
Study Sites (18)
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