Precision Therapies for Childhood Cancer

Recruiting at 15 trial locations

Overseen By International Study 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

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new medications targeting childhood cancers based on each patient's tumor profile. Specifically, it evaluates Irinotecan, Paxalisib (a new potential drug), Pimasertib, and Temozolomide for tumors unresponsive to standard treatments. Patients with a solid tumor, CNS tumor, or lymphoma that has worsened despite treatment might be suitable candidates. Participants must handle follow-ups and manage any side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to receive potentially groundbreaking therapies.

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.

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

Research shows that the treatments tested in this trial for childhood cancer have different safety profiles.

For Irinotecan, studies have found its use in children with solid tumors, but it can cause serious side effects like dehydration. These side effects differ from those in adults, so careful monitoring is important.

With Paxalisib, research indicates that studies are ongoing to determine its safety and how children's bodies process it. These studies aim to ensure it is safe for younger patients, although detailed results are still being gathered.

Temozolomide has been studied in older children, but its safety in very young children remains unclear. It can cause blood problems and possibly lead to other cancers, so close medical supervision is necessary.

Overall, while these treatments show promise, they each have potential side effects that require careful consideration and monitoring in trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for childhood cancer because they combine drugs like Irinotecan and Temozolomide with Paxalisib, a newer drug that targets the PI3K pathway, which is often overactive in cancer cells. Unlike standard chemotherapy, which attacks all rapidly dividing cells, Paxalisib specifically aims at cancer cell growth, potentially reducing harm to healthy cells. Additionally, the combination of these drugs is designed to work in synergy, potentially enhancing overall effectiveness and offering new hope for tackling resistant cancer types.

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

Research has shown that irinotecan, one of the treatments in this trial, may help treat some childhood cancers. Specifically, it has stopped the growth of Ewing sarcoma in some children and achieved success rates up to 38% in similar cases. Paxalisib, another treatment option in this trial, has also produced positive results in treating childhood brain cancers, with some patients experiencing significant tumor shrinkage when combined with another drug. Temozolomide, also part of this trial, has been used for high-grade gliomas in children, with about 23% of patients living without cancer progression for five years. These findings suggest these treatments could be effective for childhood cancers, but individual results may vary. ^{6 7 8 9 10}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Arm C Opdualag Experimental Treatment 1 Intervention

Drug: Opdualag, a fixed dose combination of Nivolumab and Relatlimab Opdualag, a fixed-dose combination of Nivolumab 480mg and Relatlimab 160mg, intravenous, on day 1, 28 day cycle, 26 cycles.

Group II: Arm A Paxalisib Experimental Treatment 3 Interventions

Drug: Irinotecan, Drug: Temozolomide, Drug: Paxalisib. Irinotecan starting at 50mg/m2/day, intravenous, on days 1-5, 28 day cycle, 13 cycles. Temozolomide starting at 150mg/m2/day, oral, on days 1-5, 28 day cycle, 13 cycles. Paxalisib starting at 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+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Stand Up To Cancer

Collaborator

Trials

53

Recruited

40,100+

Published Research Related to This Trial

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 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]

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]

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 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]

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]

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, 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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4552408/

Fifteen years of irinotecan therapy for pediatric sarcoma

Response rates as high as 38 % for Ewing sarcoma/primitive neuroectodermal tumor and 16 % for rhabdomyosarcoma have been reported [9]. However, ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC2903337/

A Pediatric Brain Tumor Consortium Study - PMC

Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a pediatric brain tumor consortium ...

3.

researchgate.net

researchgate.net/publication/12169016_Irinotecan_CPT-11_Recent_Developments_and_Future_Directions-Colorectal_Cancer_and_Beyond

Irinotecan (CPT-11): Recent Developments and Future ...

Irinotecan has shown activity against colorectal, oesophageal, gastric, non-small-cell, and small-cell lung cancers, leukemia, lymphomas, and ...

4.

cancerresearchuk.org

cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-irinotecan-for-children-and-young-people-with-high-risk-ewings-sarcoma-or-primitive-neuroectodermal-tumour

A trial looking at irinotecan for children and young people ...

Summary of results. The trial team found that irinotecan alone had stopped the growth of Ewings sarcoma in some children. This trial recruited 23 children.

5.

aacrjournals.org

aacrjournals.org/cancerres/article/83/7_Supplement/6716/719588/Abstract-6716-Preclinical-evaluation-of-nano

Preclinical evaluation of nano-liposomal irinotecan in pediatric ...

Irinotecan (IRN) has shown efficacy in diverse pediatric cancers where children are often treated on an extended low-dose schedule rather ...

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2014/020571s048lbl.pdf

CAMPTOSAR (Irinotecan) Injection, intravenous infusion

The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration ...

7.

fda.gov

fda.gov/files/drugs/published/N20-571S023-Irinotecan-Clinpharm-BPCA.pdf

N20-571S023 Irinotecan Clinpharm

Irinotecan was evaluated in pediatric cancer patients for treatment of solid tumors, including. CNS tumors and well as rhabdomyosarcoma, in this submission.

8.

cdn.caymanchem.com

cdn.caymanchem.com/cdn/msds/14180m.pdf

Safety Data Sheet

Germ cell mutagenicity 2 H341 Suspected of causing genetic defects. Reproductive toxicity 1B H360 May damage fertility or the unborn child. d. ~ ...

9.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12184384/

Safety evaluation of irinotecan - PubMed Central

This pharmacovigilance study is the first to comprehensively quantify and visualize the safety profile of irinotecan using data from the FAERS and JADER ...

10.

clinicaltrials.gov

clinicaltrials.gov/study/NCT00016861

Irinotecan in Treating Children With Refractory or ...

Also called a data safety and monitoring board, or DSMB. Early Phase 1 (formerly listed as Phase 0). A phase of research used to describe ...