Ribociclib + Topotecan + Temozolomide for Neuroblastoma
Recruiting in Palo Alto (17 mi)
+13 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Novartis Pharmaceuticals
Must not be taking: CYP3A4/5 drugs
Disqualifiers: Heart disease, QTc prolongation, others
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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).
Do I have to stop taking my current medications for the trial?
The trial requires that you stop taking medications that are mainly metabolized by CYP3A4/5 with a narrow therapeutic index, as well as strong inducers or inhibitors of CYP3A4/5, herbal preparations, and dietary supplements. If you are on such medications, you may need to discuss alternatives with your doctor.
What data supports the effectiveness of the drug combination Ribociclib, Topotecan, and Temozolomide for treating neuroblastoma?
Research shows that combinations including temozolomide and topotecan have been used in treating neuroblastoma, with some studies indicating activity against relapsed or refractory cases. For example, topotecan combined with other drugs has been tested in high-risk neuroblastoma patients, and temozolomide has shown effectiveness when used with irinotecan in similar conditions.
12345Is the combination of Ribociclib, Topotecan, and Temozolomide safe for humans?
The combination of Temozolomide with other drugs has been studied in neuroblastoma and was generally well tolerated, showing a favorable safety profile in preclinical studies. However, specific safety data for the combination of Ribociclib, Topotecan, and Temozolomide is not available in the provided research.
14567How is the drug combination of Ribociclib, Topotecan, and Temozolomide unique for treating neuroblastoma?
This drug combination is unique because it includes Ribociclib, which is not commonly used in existing neuroblastoma treatments. Ribociclib works by inhibiting proteins that help cancer cells grow, potentially offering a new approach when combined with Topotecan and Temozolomide, which are already used in various combinations for this condition.
128910Eligibility Criteria
This trial is for children and young adults aged 12 months to 21 years with certain types of solid tumors, including neuroblastoma, that have not responded to standard treatments. Participants need a life expectancy over 12 weeks, must understand the study and consent to it, have adequate organ function, and agree to use effective contraception if applicable.Inclusion Criteria
I am between 1 and 21 years old.
I can understand and am willing to sign the consent form.
My liver, kidneys, and heart are functioning well.
+7 more
Exclusion Criteria
I am not on medications that strongly affect liver enzyme CYP3A4/5.
I have not had major surgery in the last 2 weeks.
I have been treated with a CDK4/6 inhibitor before.
+11 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase I-Part A (Dose Finding)
A dose finding phase to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.
Up to 28 days
Cycle 1 day 1 and 15; Cycle 2 Day 15
Phase I-Part B (Multiple Expansion Cohorts)
Multiple expansion cohorts to confirm RP2D and assess preliminary antitumor activity and safety of ribociclib in combination with TOTEM.
Up to 12 months
Phase II
Double-blind, randomized, placebo-controlled trial to assess efficacy and safety in participants with relapsed or refractory neuroblastoma.
Up to 42 months
Follow-up
Participants are monitored for safety and effectiveness after treatment.
Up to 42 months
Participant Groups
The trial is testing the combination of Ribociclib with Topotecan and Temozolomide (TOTEM) in pediatric patients. It aims to find out how safe this mix is and how well it works against relapsed or refractory neuroblastoma and other solid tumors in kids.
8Treatment groups
Experimental Treatment
Placebo Group
Group I: Phase II- Ribociclib+Topotecan and TemozolomideExperimental Treatment3 Interventions
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.
Group II: Phase I-part A: Ribociclib + Topotecan and TemozolomideExperimental Treatment3 Interventions
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.
Group III: Phase I-Part B: r/r MRT CohortExperimental Treatment3 Interventions
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
Group IV: Phase I-Part B: r/r HGG CohortExperimental Treatment3 Interventions
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
Group V: Phase I- Part B: r/r RMS CohortExperimental Treatment3 Interventions
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
Group VI: Phase I- Part B: r/r NB CohortExperimental Treatment3 Interventions
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
Group VII: Phase I- Part B: r/r MB CohortExperimental Treatment3 Interventions
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
Group VIII: Phase II: Placebo+Topotecan and TemozolomidePlacebo Group3 Interventions
Participants with r/r NB will be treated ribociclib matching placebo in combination with topotecan and temozolomide
Ribociclib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:
🇪🇺 Approved in European Union as Kisqali for:
- Breast cancer
🇺🇸 Approved in United States as Kisqali for:
- Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
🇨🇦 Approved in Canada as Kisqali for:
- Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
🇯🇵 Approved in Japan as Kisqali for:
- Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
🇨🇭 Approved in Switzerland as Kisqali for:
- Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Cohen Children's Medical Center of New YorkNew Hyde Park, NY
Dana Farber Cancer InstituteBoston, MA
St Jude s Childrens Research HospitalMemphis, TN
Levine Childrens HospitalCharlotte, NC
More Trial Locations
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Who Is Running the Clinical Trial?
Novartis PharmaceuticalsLead Sponsor
Innovative Therapies For Children with Cancer ConsortiumCollaborator
References
Vincristine, Irinotecan, and Temozolomide in Patients With Relapsed/Refractory Neuroblastoma. [2022]The combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed and refractory neuroblastoma (NB).
Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. [2018]Relapsed high-risk neuroblastoma patients still have a poor prognosis. This phase-II trial assessed a new topotecan containing chemotherapy approach in patients with active disease.
Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. [2021]Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.
Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. [2021]The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children's Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF.
FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway. [2021]Neuroblastoma (NB) is the most common extra-cranial solid tumor in childhood. Poor outcomes for children with advanced disease underscore the need for novel therapeutic strategies. FTY720, an immunomodulating drug approved for multiple sclerosis, has been investigated in oncology with promising preclinical activities. To date, its effect in NB has not been explored. Herein we describe our preclinical experience with FTY720, alone or in combination with topotecan, and its putative mechanism of action in NB.
Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. [2020]High-risk neuroblastoma, a predominantly TP53 wild-type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography-mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post-treatment with maximal p53 pathway activation 3-6 h post-treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y-Luc and NB1691-Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.
Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. [2019]In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.
A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. [2020]A Phase II trial in children with advanced neuroblastoma was carried out in five Italian institutions to evaluate the antitumor activity and tolerability of topotecan followed by vincristine and doxorubicin.
Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. [2022]Single-agent topotecan (TOPO) and combination topotecan and cyclophosphamide (TOPO/CTX) were compared in a phase II randomized trial in relapsed/refractory neuroblastoma. Because responders often underwent further therapies, novel statistical methods were required to compare the long-term outcome of the two treatments.
Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study. [2020]Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients.