Chemotherapy Combo for Desmoplastic Small Round Cell Tumor

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Pregnancy, CNS metastases, Hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of chemotherapy drugs—irinotecan, temozolomide, and bevacizumab (also known as Avastin)—to evaluate their effects on Desmoplastic Small Round Cell Tumor (DSRCT), a rare cancer. Researchers aim to understand the benefits and side effects of adding these drugs to the current DSRCT treatment plan. The trial seeks participants who are newly diagnosed with DSRCT and have not yet started other treatments. Participants can expect a focus on how this drug mix affects their condition and overall health. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, your hypertension must be well controlled on stable doses of medication for at least two weeks before joining the trial.

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

Research has shown that the combination of bevacizumab, irinotecan, and temozolomide has been studied for safety in treating Desmoplastic Small Round Cell Tumor (DSRCT). These drugs, when used together, are generally well-tolerated. A pilot study found that this combination has manageable side effects.

Irinotecan and temozolomide have also been tested together in various studies for DSRCT and similar tumors. These studies indicate that most side effects, such as nausea, tiredness, and low blood counts, are predictable and manageable with supportive care from doctors.

Overall, while some side effects exist, these treatments have been used in other studies, and their safety is well-known. This suggests that the combination is reasonably safe, but as this is an early-phase study, much remains to be learned about its effects in this specific setting. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the chemotherapy combination of bevacizumab, irinotecan, and temozolomide for Desmoplastic Small Round Cell Tumor (DSRCT) because it introduces a new approach to tackling this aggressive cancer. Unlike traditional treatments that primarily rely on surgery and radiation, this regimen incorporates bevacizumab, which targets the tumor's blood supply, potentially starving the cancer cells. Additionally, the combination with irinotecan and temozolomide may enhance the overall effectiveness by exploiting different mechanisms to attack the tumor from multiple angles. This multi-drug strategy aims to improve outcomes for patients who have limited effective options.

What evidence suggests that this chemotherapy combination could be effective for Desmoplastic Small Round Cell Tumor?

Research has shown that a combination of three drugs—irinotecan, temozolomide, and bevacizumab—may effectively treat Desmoplastic Small Round Cell Tumor (DSRCT). In one study, all patients survived for at least one year, and 61% survived for three years. This trial will evaluate the combination of irinotecan, temozolomide, and bevacizumab as part of a chemotherapy regimen. Irinotecan, when used with other drugs, can significantly shrink tumors. The combination of temozolomide and irinotecan led to partial tumor reduction in 50% of patients, lasting 8 to 9 months. Adding bevacizumab to other treatments can help improve overall results. ^{4 6 7 8 9}

Who Is on the Research Team?

Emily Slotkin, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for young patients (1-30 years old) with a rare cancer called Desmoplastic Small Round Cell Tumor who haven't had previous cancer treatments. They need to have good blood counts, controlled blood pressure, and proper liver, heart, and kidney function. Participants must not be pregnant or breastfeeding and should agree to use contraception.

Inclusion Criteria

I have been newly diagnosed with DSRCT and have not received any treatment.

Patients must consent to an indwelling central venous catheter

My high blood pressure is stable with medication for at least two weeks.

Exclusion Criteria

Pregnant or breastfeeding females

I have had chemotherapy or radiotherapy before.

I do not have a bleeding disorder or significant blood clotting issues without taking blood thinners.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive irinotecan, temozolomide, and bevacizumab in combination with high dose alkylator based therapy

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Irinotecan
• Temozolomide

Trial Overview The study tests adding irinotecan, temozolomide, and bevacizumab to the existing chemotherapy regimen for DSRCT. The goal is to assess the effects of this combination on both the patient's health and their response to the tumor treatment.

How Is the Trial Designed?

Group I: Chemotherapy Experimental Treatment 1 Intervention

This is a pilot study to evaluate the acute toxicities and activity of irinotecan, temozolomide, and bevacizumab incorporated into an existing schedule of high dose alkylator based therapy in newly diagnosed patients with DSRCT.

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

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

The ECI regimen, which combines irinotecan, cisplatin, and etoposide over three days, demonstrated a high response rate of 77% in advanced-stage small-cell lung cancer patients, indicating its efficacy as a treatment option.

The maximum tolerated dose of irinotecan was established at 140 mg/m², with manageable side effects including febrile neutropenia and grade 3 diarrhea, suggesting that the regimen is well tolerated by patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of etoposide, cisplatin and irinotecan triplet in patients with advanced-stage small-cell lung cancer. Briasoulis, E., Samantas, E., Kalofonos, H., 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]

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 phase I study found that alternating weekly therapy with irinotecan/cisplatin and etoposide/cisplatin was well-tolerated by patients with small-cell lung cancer, indicating a favorable safety profile for this treatment regimen.

The combination of these drugs demonstrated significant antitumor activity, suggesting a potential clinical advantage for using this approach as a first-line therapy in small-cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-dense therapy with a novel irinotecan regimen for small-cell lung cancer. Johnson, FM., Kurie, JM., Peeples, BO., et al.[2018]

Irinotecan, when combined with cisplatin, significantly improves survival rates in previously untreated patients with extensive-stage small-cell lung cancer, showing a median progression-free survival of 6.9 months compared to 4.8 months with standard treatment (etoposide/cisplatin).

The combination therapy also resulted in a median overall survival of 12.8 months versus 9.4 months for the standard treatment, indicating that irinotecan could be a promising new option for enhancing treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan plus cisplatin in small-cell lung cancer. Sandler, A.[2018]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3975756/

Desmoplastic Small Round Cell Tumor: Report of 2 Cases ... Our cases confirm the data: case 1 only underwent biopsy and survived 13 months; case 2 had a larger cytoreduction and survived 34 months. A ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.11050

A pilot trial of irinotecan, temozolomide and bevacizumab ... Overall survival at 1 year was 100% and 3 years 61% (95% CI 25-84%). Conclusions: The combination of ITB is active in patients with DSRCT, and ...

3. journals.sagepub.com journals.sagepub.com/doi/10.1177/1179554920987107

The Role and Clinical Effectiveness of Multiline ... However, the survival outcomes of these patients are still poor, with a reported median overall survival (OS) of less than 3 years and with long ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01946529

NCT01946529 | Therapeutic Trial for Patients With Ewing ... This protocol will study treatment for Ewing sarcoma family of tumors (ESFT) and desmoplastic small round cell tumor (DSRCT). Participants with ESFT will be ...

5. ar.iiarjournals.org ar.iiarjournals.org/content/41/8/3859

Desmoplastic Small Round-cell Tumor: Retrospective ... In another study, with a median follow-up of 59.9 months, the median survival was 37.7 months, and the median disease-free survival was 15.5 months. The factors ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7865637/

Desmoplastic Small Round Cell Tumor: A Review of Main ... Bevacizumab, a VEGF-A inhibitor, was combined with irinotecan and temozolamide (ITB regimen) in the first-line treatment of DSRCT. In this single-arm pilot ...

7. aetna.com aetna.com/cpb/medical/data/600_699/0685.html

Bevacizumab for Non-Ocular Indications Desmoplastic small round cell tumor: Report of 2 cases treated with chemotherapy alone or in combination with bevacizumab. Case Rep Oncol. 2014;7(1):102-108 ...

8. go.drugbank.com go.drugbank.com/conditions/DBCOND0048978

Desmoplastic Small Round Cell Tumor (DSRCT ... - DrugBank Safety and Efficacy of CAR-T Cell Therapy for Relapsed/refractory Neuroblastoma and Desmoplastic Small Round Cell Tumors: a Single-arm, Open-label Trial. No ...

9. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.705760/full

Intra-Abdominal Desmoplastic Small Round Cell Tumor Trabectedin has been deemed safe and effective in pre-treated IDSRCT patients who were refractory to conventional chemotherapy and resection (45, 54). TABLE 4.