Liposomal Irinotecan-Based Therapy for Rhabdomyosarcoma

Recruiting at 2 trial locations

Overseen By Alberto Pappo, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Prior chemotherapy, Pregnancy, Breastfeeding, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

Duration: 42 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I-II study to determine safety and efficacy of combining liposomal irinotecan with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan with temozolomide and vincristine alternating with VAC in high-risk patients and the chemotherapy combinations when given with concomitant radiation therapy in intermediate and high risk patients. Primary Objective * The primary objective of the Phase I part is to estimate the maximum tolerated doses (MTDs) and recommended Phase II doses (RP2Ds) of combining liposomal irinotecan with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan with temozolomide and vincristine alternating with VAC in high-risk patients and the chemotherapy combinations when given with concomitant radiation therapy in intermediate and high risk patients. * Estimate event-free survival for intermediate-risk participants treated with VAC and vincristine and liposomal irinotecan (VLI) with the addition of maintenance therapy with vinorelbine and cyclophosphamide. * Estimate the event-free survival for high-risk patients treated with VAC and vincristine, liposomal irinotecan, and temozolomide with the addition of maintenance therapy with vinorelbine and cyclophosphamide. * Estimate the local recurrence rate for unresected intermediate- and high-risk patients with initial tumor size with ≥5 cm randomized to between 59.4 GyRBE and 68 GyRBE total proton radiation dose while receiving VAC/VLI (intermediate-risk) or VAC/VLI plus temozolomide (high-risk) and maintenance therapy. Secondary Objectives * To assess the relation between pharmacogenetic variation in CEP72 genotype and vinca alkaloid (vincristine; vinorelbine) disposition in children with rhabdomyosarcoma. * To assess the relation between the pharmacogenetic variation in drug metabolizing enzymes and drug transporters, and the pharmacokinetics of vinca alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma. * To assess the extent of inter-patient variability in the pharmacokinetics of vinca alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma, and explore possible associations between drug disposition and patient specific covariates (e.g., age, sex, race, weight). * Estimate the cumulative incidence of local recurrence in patients with low-risk disease treated with either no adjuvant radiation or minimal volume radiation.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants should not have received any prior chemotherapy or full course radiation therapy for rhabdomyosarcoma, except in emergency situations.

What data supports the effectiveness of the drug irinotecan for treating rhabdomyosarcoma?

Research shows that irinotecan, alone or with vincristine, has antitumor activity in treating metastatic rhabdomyosarcoma in children. Additionally, irinotecan combined with radiation therapy has shown effectiveness in controlling the disease locally. ^{1 2 3 4 5}

Is liposomal irinotecan-based therapy safe for humans?

Studies have shown that irinotecan, when used alone or in combination with other drugs like vincristine and cyclophosphamide, has been tested for safety in children with rhabdomyosarcoma. While it is active against the cancer, it can cause side effects, but these are generally manageable. The combination of vincristine and irinotecan with other drugs resulted in less severe blood-related side effects compared to some other treatments. ^{1 2 3 5 6}

What makes this treatment for rhabdomyosarcoma unique?

This treatment is unique because it combines liposomal irinotecan, which is a form of the drug irinotecan that is encased in tiny fat-like particles to improve delivery to cancer cells, with other therapies like cyclophosphamide, vincristine, and various forms of radiation. This combination aims to enhance the effectiveness of treatment by using multiple approaches to target the cancer. ^{1 2 3 5 7}

Research Team

Alberto S. Pappo

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

Children and young adults under 22 with newly diagnosed rhabdomyosarcoma (RMS), including specific subtypes, who haven't had prior chemotherapy or radiation (except in emergencies). They must have proper kidney, liver, and bone marrow function, not be pregnant or breastfeeding, agree to use contraception if of reproductive potential, and have no severe lung disease.

Inclusion Criteria

to < 2 years 0.6 0.6

I do not have any ongoing, untreated infections.

My cancer is at Stage 2, Group I or II.

Exclusion Criteria

Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for at least 3 months after treatment is completed.

I am not pregnant and have a negative pregnancy test.

I have had radiation therapy at the site where my cancer started.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 42 weeks of VAC chemotherapy alternating with VLI or VLIT chemotherapy, along with surgery and radiation therapy

42 weeks

Regular visits for chemotherapy administration and monitoring

Maintenance Therapy

Participants receive 6 months of maintenance chemotherapy with vinorelbine and oral cyclophosphamide

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on event-free survival and local recurrence rate

2 years

Treatment Details

Interventions

• Cyclophosphamide
• Filgrastim, peg-filgrastim
• Liposomal irinotecan
• Proton beam radiation or external beam radiation or brachytherapy
• Surgical Resection
• Temozolomide
• Vincristine
• Vinorelbine

Trial Overview The trial is testing the safety and effectiveness of liposomal irinotecan combined with other cancer drugs like vincristine and cyclophosphamide. It's for patients with intermediate to high-risk RMS. The study will also look at how well these drug combinations work when given alongside different types of radiation therapy.

Participant Groups

Group I: Low -risk Experimental Treatment 5 Interventions

The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.

Group II: Intermediate-risk Experimental Treatment 8 Interventions

The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.

Group III: High-risk Experimental Treatment 9 Interventions

The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

In a study involving 69 pediatric patients with newly diagnosed metastatic rhabdomyosarcoma, the combination of vincristine and irinotecan showed a high response rate of 70% for partial or complete responses, significantly outperforming irinotecan alone, which had a response rate of 42%.

The combination therapy demonstrated a low progressive disease rate of only 8%, and while irinotecan was associated with gastrointestinal toxicities, the differing mechanisms of action and toxicity profiles suggest that this combination could be a promising treatment option for further research in intermediate-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. Pappo, AS., Lyden, E., Breitfeld, P., et al.[2018]

In a study of 60 patients with newly diagnosed intermediate- or high-risk rhabdomyosarcoma, the combination of irinotecan and carboplatin with radiotherapy showed a high local control rate of 89% over a median follow-up of 32 months.

The treatment was well-tolerated, with lower rates of severe mucositis compared to historical data, indicating that this combination may be a safe and effective option for managing RMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent radiation with irinotecan and carboplatin in intermediate- and high-risk rhabdomyosarcoma: a report on toxicity and efficacy from a prospective pilot phase II study. Dharmarajan, KV., Wexler, LH., Wolden, SL.[2018]

In a study of 61 pediatric patients with newly diagnosed metastatic rhabdomyosarcoma, the combination of topotecan and cyclophosphamide showed an overall response rate of 47%, indicating significant antitumor activity.

Despite the promising response to treatment, the 3-year disease-free survival rate was only 10%, highlighting the need for improved therapies for children with metastatic rhabdomyosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study. Walterhouse, DO., Lyden, ER., Breitfeld, PP., et al.[2015]

Topotecan demonstrated a 46% overall response rate in treating metastatic rhabdomyosarcoma (RMS) in 48 patients under 21 years old, with a notably higher response rate of 65% in those with alveolar RMS compared to 28% in embryonal RMS.

The treatment was associated with manageable toxicities, primarily neutropenia (67%) and anemia (33%), suggesting that topotecan has a favorable safety profile and warrants further investigation in larger phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. Pappo, AS., Lyden, E., Breneman, J., et al.[2017]

In a phase II study involving 35 pediatric patients with recurrent or refractory rhabdomyosarcoma, irinotecan showed an overall response rate of 11.4%, with 2.9% achieving complete responses and 8.5% partial responses.

Irinotecan was generally well-tolerated, with the most common severe side effects being neutropenia (46%) and abdominal pain (17%), indicating that while the treatment had limited efficacy, it was manageable in terms of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. Vassal, G., Couanet, D., Stockdale, E., et al.[2018]

In a study involving 448 patients with intermediate-risk rhabdomyosarcoma, substituting vincristine and irinotecan (VI) for part of the standard VAC regimen did not improve event-free survival (EFS) or overall survival (OS) rates, which remained similar between the two treatment groups.

However, the VAC/VI regimen resulted in less severe hematologic toxicity and a lower cumulative dose of cyclophosphamide, suggesting it could be a safer alternative standard therapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. Hawkins, DS., Chi, YY., Anderson, JR., et al.[2020]

In a study of 19 children and adolescents with relapsed rhabdomyosarcoma (RMS), the combination therapy of vincristine, irinotecan, and temozolomide (VIT) showed a clinical benefit rate of 26.7%, indicating some effectiveness in managing the disease despite a high rate of progressive disease.

After a median follow-up of 8 months, only 10% of patients were alive without disease, suggesting that while VIT may provide some disease control, the overall prognosis remains poor for relapsed RMS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma. Setty, BA., Stanek, JR., Mascarenhas, L., et al.[2020]

References

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

Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. [2018]

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

Concurrent radiation with irinotecan and carboplatin in intermediate- and high-risk rhabdomyosarcoma: a report on toxicity and efficacy from a prospective pilot phase II study. [2018]

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

Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study. [2015]

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

Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. [2017]

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

Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. [2018]

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

Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. [2020]

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

VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma. [2020]