Precision Therapies for Childhood Cancer

Recruiting at 10 trial locations

Overseen By KOALA Manager

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Australian & New Zealand Children's Haematology/Oncology Group

Must not be taking: Corticosteroids

Disqualifiers: Symptomatic CNS tumors, Heart disease, Viral hepatitis, others

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

Compensation: Varies

Number of Visits: 28

Duration: 12 months

82 Participants Needed

Trial Summary

What is the purpose of this trial?

A companion platform trial to test novel targeted agents based on the patient's tumor profile.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must have recovered from the effects of any prior cancer treatments before joining the trial.

What data supports the effectiveness of the drug combination of irinotecan and temozolomide for childhood cancer?

Research shows that the combination of irinotecan and temozolomide has been effective in treating relapsed or refractory pediatric solid tumors, including Ewing's sarcoma and neuroblastoma. Studies have demonstrated that this drug combination is active and tolerable in children with these challenging conditions. ^{1 2 3 4 5}

What safety data exists for the treatment involving Irinotecan and Temozolomide?

Irinotecan and Temozolomide have been studied together in patients with various cancers. Some patients experienced side effects like diarrhea, low white blood cell counts (neutropenia), and low platelet counts (thrombocytopenia). Adjustments in dosing are being explored to reduce these side effects. ^{6 7 8 9 10}

What makes the drug combination of Irinotecan, Paxalisib, Pimasertib, and Temozolomide unique for childhood cancer?

This drug combination is unique because it includes Irinotecan and Temozolomide, which have shown promising results in treating relapsed or refractory pediatric solid tumors, and their combination has demonstrated enhanced effectiveness in preclinical models. Additionally, the inclusion of Paxalisib and Pimasertib may offer novel mechanisms of action that could further improve outcomes for difficult-to-treat childhood cancers. ^{1 2 6 10 11}

Research Team

David Ziegler, Prof

Principal Investigator

Sydney Children's Hospital - Australian Study Chair

Daniel Morgenstern, Dr

Principal Investigator

The Hospital for Sick Children - Canadian Study Chair

Eligibility Criteria

This trial is for children and adolescents with various types of cancer, including solid tumors and brain tumors. It's specifically designed for those whose cancer has returned. To join, participants must have a tumor profile that matches the targeted therapies being tested.

Inclusion Criteria

I can do most activities by myself, regardless of my age.

I have recovered from side effects of my previous cancer treatments.

My cancer has worsened despite treatment or lacks a standard treatment.

Exclusion Criteria

Known hypersensitivity to any study drug or component of the formulation.

I have not had major surgery in the last 3 weeks.

I have a GI condition that affects how my body absorbs pills.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of Irinotecan, Temozolomide, and Paxalisib based on their tumor profile, in 28-day cycles for up to 13 cycles

12 months

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall clinical benefit rate

5 years

Treatment Details

Interventions

• Irinotecan
• Paxalisib
• Pimasertib
• Temozolomide

Trial Overview The study is testing new drugs (Pimasertib, Paxalisib, Irinotecan, Temozolomide) tailored to the patient's specific tumor characteristics. The goal is to see if these precision medicines can effectively treat childhood cancers that have recurred.

Participant Groups

Group I: Arm A Paxalisib Experimental Treatment 1 Intervention

Drug: Irinotecan Drug: Temozolomide Drug: Paxalisib Irinotecan 50mg/m2/day, intravenous, on days 1-5, 28 day cycle, 13 cycles Temozolomide 150mg/m2/day, oral, on days 1-5, 28 day cycle, 13 cycles Paxalisib 21mg/m2 oral, daily, 28 day cycle, 13 cycles

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

Approved in United States as Camptosar for:

• Colorectal cancer

Approved in European Union as Irinotecan for:

• Colorectal cancer

Approved in Japan as Topotecin for:

• Colorectal cancer
• Small cell lung cancer

Approved in Canada as Irinotecan for:

• Colorectal cancer

Who Is Running the Clinical Trial?

Australian & New Zealand Children's Haematology/Oncology Group

Lead Sponsor

Trials

7

Recruited

6,900+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Medical Research Future Fund

Collaborator

Trials

10

Recruited

210,000+

C17 Council

Collaborator

Trials

9

Recruited

1,800+

Children's Cancer Institute Australia (CCIA)

Collaborator

Trials

1

Recruited

80+

Kazia Therapeutics Limited

Industry Sponsor

Trials

12

Recruited

1,600+

Day One Biopharmaceuticals, Inc.

Industry Sponsor

Trials

8

Recruited

1,100+

Findings from Research

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]

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]

In a phase II study involving 66 children with relapsed or refractory medulloblastoma, the combination of temozolomide and irinotecan (TEMIRI) showed an objective response rate of 32.6% after the first 4 treatment cycles, indicating some efficacy in this challenging patient population.

Despite not meeting the primary endpoint for tumor response, TEMIRI was well-tolerated, with manageable side effects, suggesting it could serve as a suitable chemotherapy backbone for future treatments involving targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study. Grill, J., Geoerger, B., Gesner, L., et al.[2021]

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]

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]

Irinotecan (CPT-11) demonstrated activity in treating recurrent malignant gliomas, with 15% of patients showing a confirmed partial response and 55% achieving stable disease for over 12 weeks, based on a study of 60 patients.

The treatment was associated with limited toxicity, primarily mild side effects like neutropenia and nausea, but the low plasma concentrations of the drug suggest that concurrent use of anticonvulsants and dexamethasone may reduce its effectiveness by enhancing drug clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan therapy in adults with recurrent or progressive malignant glioma. Friedman, HS., Petros, WP., Friedman, AH., 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]

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]

In a clinical trial involving 19 advanced cancer patients, the combination of irinotecan (CPT-11) and thalidomide resulted in a significant decrease in the metabolism of CPT-11 into its active metabolite, SN-38, during the first treatment cycle.

This reduced metabolism may explain the observed gastrointestinal toxicity reduction in patients treated with the combination, suggesting a beneficial interaction between thalidomide and CPT-11 that improves treatment tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation. Allegrini, G., Di Paolo, A., Cerri, E., et al.[2018]

In a study involving 107 patients with recurrent malignant glioma, the maximum tolerated dose (MTD) of irinotecan (CPT-11) was found to be 325 mg/m² for those taking enzyme-inducing anticonvulsants and 125 mg/m² for those not taking them, indicating significant variability in tolerance based on concurrent medications.

The combination of CPT-11 and temozolomide (TMZ) resulted in a 14% radiographic response rate, with patients showing a median time to disease progression of 54.9 weeks, suggesting that this treatment regimen may be effective for recurrent glioblastoma multiforme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. Reardon, DA., Quinn, JA., Rich, JN., et al.[2022]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Vincristine, irinotecan, and temozolomide treatment for refractory/relapsed pediatric solid tumors: A single center experience. [2019]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study. [2021]

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

Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. [2019]

5. Spain pubmed.ncbi.nlm.nih.gov

[Irinotecan plus temozolomide in refractory or relapsed pediatric solid tumors]. [2018]

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

Irinotecan therapy in adults with recurrent or progressive malignant glioma. [2022]

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

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

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

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

9. Germany pubmed.ncbi.nlm.nih.gov

Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation. [2018]

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

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. [2022]

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

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