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
- Intervention
- Topotecan
- Conditions
- Neuroblastoma
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 12
- Locations
- 4
- Primary Endpoint
- Phase 1- Part A: Percentage of participants with Dose Limiting Toxicities (DLTs) in Cycle 1
- Status
- Terminated
- Last Updated
- 6 months ago
Overview
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).
Detailed Description
The study is structured into two parts: Phase I - Part A (dose finding) and Phase I - Part B (multiple expansion cohorts). Phase II may commence following the evaluation of Phase I data, which includes safety, tolerability, efficacy, pharmacokinetics, and biomarker data. Additionally, other emerging data that could influence the treatment landscape will be considered before initiating Phase II in patients with relapsed or refractory neuroblastoma (NB) and/or other tumors studied in Phase I. \- Phase I - Part A (dose finding): This phase aims to determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM. Due to the early termination of the trial, Phase I - Part B (multiple expansion cohorts) and Phase II (double-blind, randomized, placebo-controlled in relapsed or refractory NB) were not initiated.
Investigators
Eligibility Criteria
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.
- •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
- •Medulloblastoma (for Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH)
- •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.
- •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
- •Rhabdomyosarcoma (for Phase I) independent of fusion status and subtype
- •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:
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
Arms & Interventions
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.
Intervention: Topotecan
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.
Intervention: Temozolomide
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.
Intervention: Ribociclib
Outcomes
Primary Outcomes
Phase 1- Part A: Percentage of participants with Dose Limiting Toxicities (DLTs) in Cycle 1
Time Frame: Up to 28 days
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.
Secondary Outcomes
- Plasma concentrations of ribociclib (Phase I-Part A)(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)(Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days)
- Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A)(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)(Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days)
- Percentage of participants with dose interruptions and dose reductions (Phase I-Part A)(Up to 12 months)