Oral Irinotecan + Temozolomide for Pediatric Solid Cancers

Recruiting at 9 trial locations

Overseen By Neil Sankar, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Valent Technologies, Inc.

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Severe allergies, Pregnancy, Infections, others

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

Compensation: Varies

Number of Visits: 2

Duration: 17 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of oral medications, irinotecan (also known as VAL-413) and temozolomide, to evaluate their safety and effectiveness for children and young adults with solid tumors such as neuroblastoma and rhabdomyosarcoma. Researchers aim to determine the best administration method and assess their efficacy in cases where standard treatments have failed. Participants must have a solid tumor diagnosis and no current effective treatment options. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting, such as strong inducers or inhibitors of specific enzymes (CYP3A4 and UGT1A1), and medications that affect platelet function. If you're on these, you may need to stop them 1-2 weeks before the trial.

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

Research has shown that the combination of VAL-413 (Orotecan®) and temozolomide has been tested for safety in children with relapsed high-risk neuroblastoma. Early results suggest that this combination is generally well-tolerated. Some children experienced side effects, which are common in cancer treatments, including nausea, diarrhea, and low blood counts. However, proper care managed these side effects. As this is an early-phase study, researchers are closely monitoring for any serious issues. Since temozolomide is already an approved drug for other conditions, its safety is somewhat understood, but the combination with VAL-413 remains under study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about VAL-413 (Orotecan®) combined with Temozolomide for pediatric solid cancers because it offers a novel oral delivery method that could be more convenient and less invasive than traditional intravenous options. Unlike other treatments, Orotecan® includes an oral preparation of irinotecan (IRN-IVPO), which could simplify administration and improve patient comfort. The study explores different dosages (75, 90, and 110 mg/m²/day) to optimize effectiveness and minimize side effects, offering potential improvements over the existing standard of care.

What evidence suggests that this trial's treatments could be effective for pediatric solid cancers?

Research shows that a combination of two medicines, oral irinotecan (VAL-413, also known as Orotecan®) and temozolomide, may help treat solid tumors in children. In this trial, participants will receive different dosages of VAL-413—either 75 mg/m²/day, 90 mg/m²/day, or 110 mg/m²/day—alongside temozolomide. Children with these recurring tumors have shown positive results with this treatment. Studies suggest that this combination can be effective for hard-to-treat cancers like neuroblastoma and rhabdomyosarcoma. The medicine comes in a flavored, liquid form to make it easier for children to take. While more research is needed to confirm these early results, the initial findings are promising. ^{2 3 4 5 6}

Who Is on the Research Team?

Javier Oesterheld, M.D.

Principal Investigator

Atrium Health Levine Children's Hospital - Carolinas Medical Center

Lars Wagner, MD

Principal Investigator

Duke University Children's Hospital & Health Center

James Geller, MD

Principal Investigator

Cincinnati Children's Hospital Medical Center (CCHMC)

Patrick Thompson, M.D.

Principal Investigator

UNC Chapel Hill - North Carolina Cancer Hospital

AeRang Kim, MD, PhD

Principal Investigator

Children's National Hospital - Washington, DC

Kieuhoa T. Vo

Principal Investigator

UCSF - Mission Bay, Benioff Children's Hospital

Meghann McManus, D.O.

Principal Investigator

Sarah Cannon Research Institute, Pediatric Hematology & Oncology

Kyle Jackson, M.D.

Principal Investigator

Indiana University School of Medicine, Riley Hospital for Children

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 30 with recurrent solid tumors like neuroblastoma or Ewing sarcoma. They must have a certain level of physical ability, no uncontrolled infections, not be pregnant, and agree to use contraception. Participants need normal organ function and can't join if they've had severe allergic reactions to specific drugs or are on certain medications.

Inclusion Criteria

My current cancer treatment options do not include a cure or significantly extend life with good quality.

I don't need to have measurable disease to join this study.

Peripheral absolute neutrophil count (ANC) ≥ 1,000/µL

Exclusion Criteria

I am not taking any medication that affects blood clotting, except for acetaminophen.

I have not taken strong medication inducers like phenobarbital or St. John's Wort in the last 2 weeks.

Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive VAL-413 (Orotecan®) with Temozolomide for 5 consecutive days every 21-day cycle, up to 17 cycles

17 months

Visits on Day 1 of each cycle

Pharmacokinetic Assessment

Serum samples collected to characterize pharmacokinetic profiles of Orotecan® and conventional irinotecan

1 month

Samples collected on Days 1 and 4 during Cycle 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Temozolomide
• VAL-413

Trial Overview The study tests the safety and effectiveness of a flavored oral form of Irinotecan (VAL-413) combined with Temozolomide in treating pediatric solid tumors. It's designed to see how well patients tolerate this new formulation and measure its impact on their cancer.

How Is the Trial Designed?

Group I: 90 mg/m2/day VAL-413 (Orotecan®) Experimental Treatment 2 Interventions

Orotecan® at 90 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.

Group II: 75 mg/m2/day VAL-413 (Orotecan®) Experimental Treatment 2 Interventions

In the event the 90 mg/m2/day starting dose is not tolerable due to toxicity, a lower starting dose of 75 mg/m2/day may be implemented. Orotecan® at 75 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.

Group III: 110 mg/m2/day VAL-413 (Orotecan®) Experimental Treatment 2 Interventions

Orotecan® at 110 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.

Temozolomide is already approved in European Union, United States for the following indications:

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

Who Is Running the Clinical Trial?

Valent Technologies, Inc.

Lead Sponsor

Trials

1

Recruited

20+

Valent Technologies, LLC

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

The maximum-tolerated dose (MTD) for the combination of temozolomide and irinotecan in pediatric patients with refractory solid tumors was determined to be 100 mg/m²/day of temozolomide and 10 mg/m²/day of irinotecan, with dose-limiting toxicities including severe diarrhea and infection observed at higher doses.

The treatment showed promising efficacy, with one complete response and two partial responses in patients with Ewing's sarcoma and neuroblastoma, particularly in those with low levels of a specific DNA repair protein, suggesting that this combination therapy could be effective for certain tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Wagner, LM., Crews, KR., Iacono, LC., et al.[2019]

A review of 5,127 reports on temozolomide (TMZ) revealed 112 cases of major hematologic adverse events (HAEs), with a significant number of these cases leading to death, highlighting the serious risks associated with this medication.

Aplastic anemia (AA) and leukemia were the most common major HAEs linked to TMZ, indicating a unique toxicity profile compared to other alkylating agents, and suggesting that patients should be informed about these risks, especially since AA can develop after a short duration of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. Villano, JL., Letarte, N., Yu, JM., et al.[2018]

The TEMIRI regimen, combining temozolomide and irinotecan, showed a 24% overall response rate in heavily pretreated metastatic colorectal cancer patients with MGMT methylation, indicating its efficacy in this specific group.

The treatment was well-tolerated, with only 16% of patients experiencing severe adverse events, and those with low or negative MGMT expression had significantly better progression-free survival compared to others.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation. Morano, F., Corallo, S., Niger, M., 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]

The combination of oral irinotecan, temozolomide, and vincristine was tested in children with relapsed solid tumors, showing that the 5-day treatment schedule (Schedule B) was well tolerated with no dose-limiting toxicities at the highest doses, indicating a safer option for patients.

The study found that this regimen provided similar drug exposure levels to those achieved with intravenous irinotecan, and it demonstrated activity in treating sarcoma, suggesting its potential effectiveness in a range of childhood solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study. Wagner, LM., Perentesis, JP., Reid, JM., et al.[2021]

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 (TMZ) is an effective DNA-methylating agent with nearly 100% oral bioavailability, allowing it to cross the blood-brain barrier and be rapidly absorbed, making it a promising treatment for brain tumors.

While TMZ shows limited effectiveness against pediatric brain tumors on its own, combining it with other treatments and assessing the methylation status of specific genes may enhance its efficacy and should be explored in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of temozolomide in pediatric brain tumors. Barone, G., Maurizi, P., Tamburrini, G., et al.[2022]

In a study of 32 pediatric patients with refractory or relapsed solid tumors, the combination of irinotecan and temozolomide resulted in a positive response in 33% of evaluable patients, with 2 achieving complete remission and 8 achieving partial remission.

The treatment was well tolerated, with only 28% of the 180 treatment cycles resulting in toxicity, and severe side effects (grade III-IV) occurring in just 8% of cases, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Irinotecan plus temozolomide in refractory or relapsed pediatric solid tumors]. Hernández-Marqués, C., Lassaletta-Atienza, A., Ruiz Hernández, A., et al.[2018]

In a study of 34 children with heavily pretreated refractory/relapsed solid tumors, the combination of vincristine, irinotecan, and temozolomide showed a 26.4% objective response rate, with particularly promising results in Ewing sarcoma patients (40% response).

The treatment was generally well tolerated, although diarrhea was a common side effect, with 10% of treatment courses resulting in severe cases (grade 3-4).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vincristine, irinotecan, and temozolomide treatment for refractory/relapsed pediatric solid tumors: A single center experience. Büyükkapu Bay, S., Kebudi, R., Görgün, O., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04337177

Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With ... A pilot pharmacokinetic trial to determine the safety and efficacy of a flavored, orally administered irinotecan VAL-413 (Orotecan®) given with temozolomide ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2667827/

Phase I Trial of Oral Irinotecan and Temozolomide for ... Results from a recent study using temozolomide ... Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS10073

A pilot clinical study of oral irinotecan HCl (VAL-413) in ... A pilot clinical study of oral irinotecan HCl (VAL-413) in patients with recurrent pediatric solid tumors. Authors: Jeffrey A. Bacha, Dennis ...

4. edisononcology.com edisononcology.com/edison-oncology-reports-promising-interim-data-from-ongoing-orotecan-clinical-trial-for-recurrent-pediatric-cancers

Edison Oncology Reports Promising Interim Data from ... The current clinical trial is designed to evaluate safety, tolerability and efficacy of Orotecan given with oral temozolomide for treatment of recurrent ...

5. cincinnatichildrens.org cincinnatichildrens.org/service/c/clinical-trials/studies/val-10-001

Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With ... A pilot pharmacokinetic trial to determine the safety and efficacy of a flavored, orally administered irinotecan VAL-413 (Orotecan®) given with temozolomide.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-04333

Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With ... A pilot pharmacokinetic trial to determine the safety and efficacy of a flavored, orally administered irinotecan VAL-413 (Orotecan®) given with temozolomide.