Ribociclib + Topotecan + Temozolomide for Neuroblastoma

Recruiting at 16 trial locations

Overseen By Novartis Pharmaceuticals

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Novartis Pharmaceuticals

Must not be taking: CYP3A4/5 drugs

Disqualifiers: Heart disease, QTc prolongation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 1

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of a combination of three drugs—ribociclib (Kisqali), topotecan, and temozolomide—in treating children and young adults with certain types of solid tumors. These include neuroblastoma, medulloblastoma, high-grade glioma, malignant rhabdoid tumors, and rhabdomyosarcoma, which have not responded to standard treatments. The trial seeks participants with these specific conditions who have not found success with existing therapies. This trial might be suitable for those dealing with these conditions when standard treatments aren't effective. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of ribociclib, topotecan, and temozolomide has been studied for treating certain cancers. Although specific data on this exact combination is limited, evidence indicates that temozolomide, when used with other drugs, is generally well tolerated. This suggests it might be safe for treating neuroblastoma, a type of cancer that develops in nerve tissue.

In studies where these drugs are used alone or in other combinations, patients have shown varying levels of tolerance. The trial phase under consideration is an early one, with the primary goal of testing the safety and determining the correct dose of the drug combination. Early trials like this usually involve fewer participants to allow close monitoring of the treatment's effects.

It's important to know that while these drugs aim to fight cancer, they can also cause side effects. Such studies are crucial to ensure treatments are safe and effective before wider use. For concerns or questions, discussing them with the trial team or a doctor is advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ribociclib, topotecan, and temozolomide for treating neuroblastoma because it offers a novel approach compared to existing therapies. While most treatments for neuroblastoma, like surgery, chemotherapy, and radiation, target cancer cells through more traditional methods, ribociclib acts as a CDK4/6 inhibitor, which can halt the division of cancer cells at a specific checkpoint in the cell cycle. This mechanism, combined with the DNA-damaging effects of topotecan and temozolomide, could potentially enhance the treatment's effectiveness, especially in resistant or relapsed cases. By combining these drugs, researchers aim to determine the maximum tolerated dose and the recommended phase 2 dose, potentially offering a more targeted and potent treatment option for aggressive cancers like neuroblastoma.

What evidence suggests that this trial's treatments could be effective for neuroblastoma?

This trial will evaluate the combination of three drugs—ribociclib, topotecan, and temozolomide, known as TOTEM—for treating neuroblastoma that has recurred or is difficult to treat. Research has shown that similar drug combinations effectively shrink tumors. Ribociclib stops proteins that help cancer cells grow, while topotecan and temozolomide are chemotherapy drugs that kill cancer cells. Early results suggest this combination could improve outcomes for children with challenging neuroblastoma and other solid tumors. Further studies are underway to confirm these results and determine the optimal doses. ^{1 2 3 5 6}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: 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.

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+

Published Research Related to This Trial

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]

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 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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05429502

NCT05429502 | Study of Efficacy and Safety of Ribociclib ... 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 ...

2. clinicaltrials.eu clinicaltrials.eu/trial/study-on-ribociclib-topotecan-and-temozolomide-for-children-and-young-adults-12-months-21-years-with-relapsed-or-refractory-neuroblastoma-and-solid-tumors/

Study on Ribociclib, Topotecan, and Temozolomide for ... This clinical trial investigates the safety and efficacy of combining Ribociclib, Topotecan, and Temozolomide in treating relapsed or ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03144

Study of Efficacy and Safety of Ribociclib (LEE011) in ... 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 ...

4. withpower.com withpower.com/trial/phase-2-neuroblastoma-7-2022-6c0cd

Ribociclib + Topotecan + Temozolomide for Neuroblastoma The combination of vincristine, irinotecan, and temozolomide (VIT) was found to be an effective treatment for relapsed or refractory neuroblastoma, achieving an ...

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.21.01152

Phase I or II Study of Ribociclib in Combination With ... The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05429502/study-of-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

Study of Efficacy and Safety of Ribociclib (LEE011) in ... 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