Eribulin + Irinotecan + Temozolomide for Cancer

Overseen By Fiorela Hernandez Tejada, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Investigational drugs, Anti-cancer agents

Disqualifiers: Significant organ dysfunction, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—eribulin (Halaven), irinotecan, and temozolomide—to determine the optimal dose for treating certain solid tumors that have recurred or are resistant to treatment. The researchers aim to evaluate how well these drugs work together in individuals with specific cancers, such as Ewing's sarcoma or rhabdomyosarcoma. They seek participants with a solid tumor that has returned or is unresponsive to current treatments, including those who may have previously tried irinotecan or temozolomide individually. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants an opportunity to contribute to early-stage cancer research.

Will I have to stop taking my current medications?

The trial requires that you stop taking other anti-cancer medications and investigational drugs before participating. The protocol does not specify about other types of medications, so it's best to discuss your current medications with the trial team.

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

Research has shown that eribulin, used alone or with irinotecan, has been tested in past studies, providing some information about its safety. Specifically, eribulin and irinotecan have been effective against various solid tumors in children, such as Ewing sarcoma and rhabdomyosarcoma. These drugs have been administered to patients before, offering some safety data.

However, earlier studies found that using eribulin and irinotecan together was less effective and had more safety issues compared to temozolomide. While detailed safety information on using all three drugs together (eribulin, irinotecan, and temozolomide) is lacking, each drug has been used in past treatments, providing some background on their safety.

Since this trial is in the early stages, it primarily aims to determine the safe dosage. Researchers will monitor how well patients tolerate the combination, helping to identify potential side effects and adjust doses to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of eribulin, irinotecan, and temozolomide for treating certain cancers because it offers a unique approach compared to traditional treatments. Unlike most standard chemotherapy options that typically target rapidly dividing cells in a less specific manner, eribulin works by disrupting microtubule dynamics, which is a critical process in cell division. This makes it potentially more effective in targeting cancer cells with fewer side effects. Additionally, combining these drugs could provide a synergistic effect, potentially enhancing their cancer-fighting abilities. This combination is particularly promising for rare and aggressive cancers like Ewing's sarcoma and rhabdomyosarcoma, where current treatment options are limited.

What evidence suggests that this trial's treatments could be effective for relapsed and/or refractory solid tumors?

This trial will evaluate the combination of eribulin, irinotecan, and temozolomide for treating certain cancers. Studies have shown that using eribulin and irinotecan together can be promising, with research indicating that they can completely shrink tumors in several studies. This combination has proven effective in models of Ewing sarcoma, a type of bone cancer. Irinotecan has also shown success against many solid tumors, including Ewing sarcoma and rhabdomyosarcoma, a cancer of the soft tissues. Although clinical data for this specific combination is limited, early studies suggest it could help with relapsed or hard-to-treat solid tumors. Participants in this trial will enroll in one of several treatment arms based on their disease type, including Ewing sarcoma, rhabdomyosarcoma, and other solid tumor histologies. ^{1 2 3 6 7}

Who Is on the Research Team?

Fiorela Hernandez Tejada, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 25 with relapsed or refractory solid tumors. Participants need proper kidney, liver, and bone marrow function, no severe infections or allergies to cephalosporins, and can't be pregnant. They must have recovered from previous treatments and not received certain drugs recently.

Inclusion Criteria

I have had irinotecan or temozolomide alone, but not together.

Total bilirubin ≤ 1.5x upper limit of normal (ULN) for age, SGPT (ALT) ≤ 3 x ULN, Serum albumin ≥ 2gm/dL

I have recovered from graft versus host disease, don't need immunosuppressants, and it's been over 3 months since my transplant.

Exclusion Criteria

I do not have an ongoing severe infection or have been treated for C. difficile recently.

Pregnancy or Breast-Feeding

My organs are functioning well enough to meet the study requirements.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding

Participants receive varying doses of eribulin to determine the maximum tolerated dose in combination with irinotecan and temozolomide

8 weeks

Dose Expansion

Participants receive the recommended dose combination based on their disease type in one of three treatment arms

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including disease response and symptom relief

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Eribulin
• Irinotecan
• Temozolomide

Trial Overview The study aims to determine the safe dose of eribulin when combined with irinotecan and temozolomide in treating stubborn solid tumors that haven't responded well to other therapies.

How Is the Trial Designed?

Group I: Arm D: Dose finding levels 0,-1 and -2 Experimental Treatment 3 Interventions

The first group of participants in this phase will receive the highest dose of eribulin. Each group of participants enrolled after that will receive a slightly lower dose of the drug. Participants in this phase will be enrolled in 1 of 3 treatment arms, based on their disease type, and will receive the recommended dose combination found in the Dose Escalation phase.

Group II: Arm C: Dose expansion- other solid tumor histologies Experimental Treatment 3 Interventions

The first group of participants in this phase will receive the highest dose of eribulin. Each group of participants enrolled after that will receive a slightly lower dose of the drug. Participants in this phase will be enrolled in 1 of 3 treatment arms, based on their disease type, and will receive the recommended dose combination found in the Dose Escalation phase.

Group III: Arm B: Dose expansion -Rhabdomyosarcoma Experimental Treatment 3 Interventions

The first group of participants in this phase will receive the highest dose of eribulin. Each group of participants enrolled after that will receive a slightly lower dose of the drug. Participants in this phase will be enrolled in 1 of 3 treatment arms, based on their disease type, and will receive the recommended dose combination found in the Dose Escalation phase.

Group IV: Arm A: Dose expansion-Ewings sarcoma Experimental Treatment 3 Interventions

The first group of participants in this phase will receive the highest dose of eribulin. Each group of participants enrolled after that will receive a slightly lower dose of the drug. Participants in this phase will be enrolled in 1 of 3 treatment arms, based on their disease type, and will receive the recommended dose combination found in the Dose Escalation phase.

Eribulin is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Halaven for:

• Locally advanced or metastatic breast cancer

Approved in United States as Halaven for:

• Metastatic breast cancer
• Liposarcoma

Approved in Japan as Halaven for:

• Breast cancer
• Soft tissue sarcoma

Approved in Canada as Halaven for:

• Metastatic breast cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

The maximum tolerated dose of irinotecan when combined with temozolomide for patients with recurrent malignant glioma is 500 mg/m², with common side effects including neutropenia, thrombocytopenia, and gastrointestinal issues.

The study found that the use of enzyme-inducing antiepileptic drugs (EIAEDs) increases the clearance of irinotecan and affects its active metabolite SN-38, but no significant pharmacokinetic interaction was observed between temozolomide and irinotecan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of temozolomide and irinotecan for recurrent malignant gliomas in patients receiving enzyme-inducing antiepileptic drugs: a north american brain tumor consortium study. Loghin, ME., Prados, MD., Wen, P., et al.[2021]

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]

Irinotecan, a derivative of camptothecin, has shown significant activity against recurrent malignant glioma in clinical trials, confirming its potential as a treatment option for this aggressive brain tumor.

Combining irinotecan with alkylating agents like BCNU or temozolomide enhances its antitumor effects, leading to ongoing Phase II trials to evaluate these combinations in adults with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. Friedman, HS., Keir, ST., Houghton, PJ.[2018]

This phase I study involving 49 patients aimed to identify the maximum tolerated doses and dose-limiting toxicities of irinotecan and temozolomide, revealing significant gastrointestinal toxicities such as diarrhea and neutropenia at certain dose levels.

Two partial responses were observed in patients with glioblastoma and head and neck cancer, indicating some efficacy of the drug combination, although the recommended doses for phase II trials are still being determined due to ongoing patient accrual.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I. Trial of irinotecan and temozolomide in patients with solid tumors. Jones, SF., Gian, VG., Greco, FA., et al.[2018]

A combination of temozolomide and irinotecan was found to be tolerable and active in treating advanced Ewing sarcoma, with 1 complete response and 3 partial responses observed among 14 evaluable patients.

The treatment regimen was manageable, with minimal myelosuppression and only 11% of courses experiencing grade 3-4 diarrhea, suggesting that home administration of irinotecan is safe and feasible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Wagner, LM., McAllister, N., Goldsby, RE., et al.[2018]

Temozolomide is a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

The combination of temozolomide and irinotecan (CPT-11) was effective in inducing complete responses in various tumors, including four neuroblastomas, two rhabdomyosarcomas, and one glioblastoma, demonstrating greater efficacy than either drug alone.

Interestingly, the synergistic effect of the two drugs was independent of tumor characteristics like MGMT or mismatch repair phenotype, and coadministration of CPT-11 reduced the toxicity of temozolomide, suggesting a safer treatment profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. Houghton, PJ., Stewart, CF., Cheshire, PJ., et al.[2022]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11847257/

Efficacy, safety, and pharmacokinetics of eribulin as ... In this report, we present results from studies of eribulin as monotherapy (Study 223) and in combination with irinotecan (the phase II part of Study 213)

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e23502

Eribulin and irinotecan for refractory or recurrent Ewing ... The effectiveness of eribulin and irinotecan in treatment of xenograft models of Ewing sarcoma is well-established but little clinical data has been reported.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7299830/

Evaluation of Eribulin Combined with Irinotecan for ... Combining eribulin with irinotecan resulted in complete tumor regressions in 5 models, whereas in these models the best response for either single drug was PR.

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/03/NCT02596503/Prot_SAP_ICF_000.pdf

COMIRB #15-0659 TITLE: A Phase I/Ib Study of Eribulin in ... In children, irinotecan has demonstrated activity in wide variety of solid tumors including Ewing sarcoma [31, 32], rhabdomyosarcoma [33-35], hepatoblastoma [36 ...

5. techrxiv.org techrxiv.org/users/644176/articles/657165/download_latex

Eribulin and irinotecan (ERII) for refractory or recurrent Ewing ... Phase I study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors. Journal of ...

6. go.drugbank.com go.drugbank.com/conditions/DBCOND0027071

Rhabdomyosarcomas (DBCOND0027071) ... Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors. Eribulin · Irinotecan. treatment, 1 / 2 ...

7. oncologynurseadvisor.com oncologynurseadvisor.com/features/challenges-and-approaches-to-recurrent-ewing-sarcoma/

Management of Recurrent Ewing Sarcoma This review addresses common questions facing the clinician and patient, and provide an update on new strategies for Ewing Sarcoma therapy.