Eribulin + Irinotecan + Temozolomide for Cancer

Overseen By Fiorela Hernandez Tejada, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

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

Trial Summary

What is the purpose of this trial?

To find the recommended dose of eribulin that can be given in combination with irinotecan and temozolomide to treat relapsed and/or refractory solid tumors.

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.

What evidence supports the effectiveness of the drug combination of Eribulin, Irinotecan, and Temozolomide for cancer?

Research shows that the combination of Irinotecan and Temozolomide has been effective in treating various cancers, including glioblastoma and neuroblastoma, with some studies indicating that the combination works better than each drug alone. This suggests potential effectiveness for the combination with Eribulin, although specific data for this exact combination is not provided. ^{1 2 3 4 5}

Is the combination of Eribulin, Irinotecan, and Temozolomide safe for humans?

The combination of Irinotecan and Temozolomide has been studied in humans, showing some dose-limiting side effects like diarrhea, low white blood cell count (neutropenia), and low platelet count (thrombocytopenia). Adjustments in dosing are being explored to improve safety, but some dosing regimens have been found intolerable due to gastrointestinal issues. ^{1 2 4 6 7}

What makes the drug combination of Eribulin, Irinotecan, and Temozolomide unique for cancer treatment?

This drug combination is unique because it combines Eribulin, which disrupts cancer cell division, with Irinotecan and Temozolomide, which have shown enhanced effects when used together, potentially offering a more effective treatment for certain cancers compared to using each drug alone. ^{1 2 4 5 8}

Research Team

Fiorela Hernandez Tejada, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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.

I am a child under the care of an organization or institution.

I haven't taken growth factors or other cancer treatments in the last 7 days.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 (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]

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]

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]

References

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

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. [2018]

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

Phase I. Trial of irinotecan and temozolomide in patients with solid tumors. [2018]

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

Temozolomide in combination with other cytotoxic agents. [2019]

4. United States 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. [2022]

5. 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]

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

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

7. United States 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. [2021]

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

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. [2018]