Ribociclib + Topotecan + Temozolomide for Neuroblastoma

Recruiting at 13 trial locations

Overseen By Novartis Pharmaceuticals

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Novartis Pharmaceuticals

Must not be taking: CYP3A4/5 drugs

Disqualifiers: Heart disease, QTc prolongation, others

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

231 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 4 5 6 7}

How 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. ^{1 2 8 9 10}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility 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.

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.

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

Treatment Details

Interventions

• Ribociclib
• Temozolomide
• Topotecan

Trial Overview 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.

Participant Groups

Group I: Phase II- Ribociclib+Topotecan and Temozolomide Experimental Treatment 3 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 Temozolomide Experimental Treatment 3 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 Cohort Experimental Treatment 3 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 Cohort Experimental Treatment 3 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 Cohort Experimental Treatment 3 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 Cohort Experimental Treatment 3 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 Cohort Experimental Treatment 3 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 Temozolomide Placebo Group 3 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

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Innovative Therapies For Children with Cancer Consortium

Collaborator

Trials

14

Recruited

2,100+

Findings from Research

The combination of vincristine, irinotecan, and temozolomide (VIT) was found to be an effective treatment for relapsed or refractory neuroblastoma, achieving an overall objective response rate of 69.6% in a study of 46 patients.

The VIT regimen was well-tolerated, with most toxicities being manageable; while some patients experienced Grade 3-4 hematologic toxicity, the regimen was still considered active and safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vincristine, Irinotecan, and Temozolomide in Patients With Relapsed/Refractory Neuroblastoma. Zhu, J., Wang, J., Sun, F., et al.[2022]

In a phase-II trial involving patients with relapsed high-risk neuroblastoma, a chemotherapy regimen including topotecan, cyclophosphamide, and etoposide showed a 61% response rate in relapsed patients and a 72% response rate in untreated patients, indicating its efficacy.

The treatment was generally well-tolerated, with significant myelotoxicity (like leukopenia and thrombocytopenia) being the main side effects, but no fatal toxicities were reported, suggesting that the benefits may outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. Simon, T., Längler, A., Harnischmacher, U., et al.[2018]

In a phase I trial involving 14 children with recurrent high-risk neuroblastoma, an all-oral regimen of irinotecan and temozolomide was found to be feasible and well tolerated, with 50% of patients showing a response or disease stabilization for three or more treatment courses.

The maximum-tolerated dose (MTD) was established at 60 mg/m2/d for oral irinotecan combined with 75 mg/m2/d of temozolomide, demonstrating similar plasma exposure levels to those seen with intravenous irinotecan, suggesting this oral combination could be a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. Wagner, LM., Villablanca, JG., Stewart, CF., et al.[2021]

The combination treatment of irinotecan, temozolomide, dintuximab, and GM-CSF (I/T/DIN/GM-CSF) showed significant antitumor activity in patients with relapsed or refractory neuroblastoma, with an overall objective response rate of 41.5% across 53 patients.

The treatment was associated with a one-year progression-free survival rate of 67.9% and an overall survival rate of 84.9%, although it also resulted in notable grade ≥ 3 toxicities, including fever/infection and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. Mody, R., Yu, AL., Naranjo, A., et al.[2021]

FTY720 shows potent anti-cancer activity against neuroblastoma (NB) in preclinical models, effectively inducing cell death and inhibiting tumor growth, especially when combined with the chemotherapy drug topotecan.

The mechanism of action for FTY720 involves the inhibition of sphingosine kinase 2 and the alteration of sphingolipid levels, leading to a unique, caspase-independent cell death pathway that may enhance treatment strategies for advanced NB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway. Li, MH., Hla, T., Ferrer, F.[2021]

Idasanutlin (RO6839921) shows promising in vivo efficacy in treating high-risk neuroblastoma, particularly when combined with temozolomide, leading to greater tumor growth inhibition and improved survival in mouse models.

The study demonstrated that RO6839921 is well tolerated and has a favorable pharmacokinetic profile, supporting its potential for further development in early phase clinical trials for neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. Chen, L., Pastorino, F., Berry, P., et al.[2020]

In a phase II trial involving 32 patients with relapsed or refractory neuroblastoma, the combination of alisertib, irinotecan, and temozolomide demonstrated significant antitumor activity, with a 21% partial response rate and a 1-year progression-free survival (PFS) rate of 34%.

The study also evaluated an alisertib oral solution, which showed higher drug exposure compared to the tablet form, suggesting it may be a more effective option for some patients, particularly those with MYCN nonamplified tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. DuBois, SG., Mosse, YP., Fox, E., et al.[2019]

In a Phase II trial involving 25 children with advanced neuroblastoma, the combination of topotecan, vincristine, and doxorubicin showed a promising overall response rate of 64%, with 4 complete responses and 12 partial responses.

The treatment was generally well tolerated, with limited toxicity primarily affecting the hematopoietic system, and only one patient experiencing dose-limiting Grade 4 liver toxicity, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Garaventa, A., Luksch, R., Biasotti, S., et al.[2020]

In a phase II trial involving 119 children with relapsed/refractory neuroblastoma, the combination of topotecan and cyclophosphamide (TOPO/CTX) showed a higher response rate (32%) compared to single-agent topotecan (19%), indicating that TOPO/CTX may be more effective in achieving initial responses.

While TOPO/CTX resulted in significantly better progression-free survival (PFS), there was no difference in overall survival (OS) between the two treatments after adjusting for subsequent therapies, suggesting that while TOPO/CTX may delay disease progression, it does not necessarily improve long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. London, WB., Frantz, CN., Campbell, LA., et al.[2022]

In a study of 107 high-risk neuroblastoma patients, an induction regimen combining topotecan and cyclophosphamide resulted in favorable treatment responses, with no patients experiencing stable disease or progression after the fifth cycle.

The treatment was well tolerated, with febrile neutropenia being the most common side effect, indicating that this regimen could be a safe and effective option for managing high-risk neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Rujkijyanont, P., Photia, A., Traivaree, C., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Vincristine, Irinotecan, and Temozolomide in Patients With Relapsed/Refractory Neuroblastoma. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

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]

10. England pubmed.ncbi.nlm.nih.gov

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]