Multimodal Therapy for Rhabdomyosarcoma

Recruiting at 3 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Pregnancy, Uncontrolled infection, Allergy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

115 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will treat participants with newly diagnosed, low, intermediate and high risk rhabdomyosarcoma (RMS) using multi-modality risk-adapted therapy with standard or intensified dose chemotherapy, radiation and surgical resection. Intermediate and high risk participants will receive an additional 12 weeks (4 cycles) of maintenance therapy with anti-angiogenic chemotherapy. PRIMARY OBJECTIVE: * Estimate event-free survival for intermediate risk participants treated with vincristine, dactinomycin and cyclophosphamide with the addition of maintenance anti-angiogenic therapy. SECONDARY OBJECTIVES: * Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection. * Maintain a high local control rate in participants treated with surgery and/or limited volume proton and photon radiation without dose escalation. * Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume. * Establish the feasibility of delivering 4 cycles of maintenance anti-angiogenic chemotherapy in intermediate and high risk patients following standard chemotherapy. * Estimate the event free survival for high risk patients receiving interval dose compressed therapy and maintenance anti-angiogenic therapy. * Define the incidence of CTC grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drugs used in the multimodal therapy for rhabdomyosarcoma?

Research shows that vincristine, dactinomycin, and cyclophosphamide are effective in treating rhabdomyosarcoma, with more than 70% of children and adolescents being cured with modern treatment approaches. Proton beam therapy is also used to reduce long-term side effects in treating childhood parameningeal rhabdomyosarcoma. ^{1 2 3 4 5}

Is the multimodal therapy for rhabdomyosarcoma generally safe in humans?

The treatments involved, such as vincristine, dactinomycin, cyclophosphamide, and proton therapy, have been studied in children with rhabdomyosarcoma and are generally considered safe, with low toxicity reported in trials. These treatments have been used in various combinations and doses, showing feasibility and manageable side effects in patients. ^{1 5 6 7 8}

What makes the multimodal therapy for rhabdomyosarcoma unique?

This treatment is unique because it combines chemotherapy drugs like vincristine, actinomycin D, and cyclophosphamide with proton beam radiation, which is a precise form of radiotherapy that can minimize damage to surrounding healthy tissues. This approach aims to improve survival rates while reducing side effects compared to traditional treatments. ^{4 6 9 10 11}

Research Team

Matthew J Krasin, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults under 22 with newly diagnosed rhabdomyosarcoma (RMS), a type of muscle cancer. They must have low, intermediate, or high-risk disease levels, be able to start chemotherapy within 6 weeks after diagnosis, and have good organ function. Pregnant or breastfeeding individuals can't join.

Inclusion Criteria

All participants and/or their parents or legal guardians must sign a written informed consent

I am starting chemotherapy within 6 weeks after my biopsy or surgery.

My bone marrow is working well.

Exclusion Criteria

Participants who fail to meet one or more of the inclusion criteria

I am scheduled for initial surgery to remove my cancer.

History of allergy to Optison(TM) contrast agent or blood products

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive chemotherapy based on their risk group. Low-risk participants receive 12 weeks of chemotherapy, intermediate-risk participants receive 12 weeks followed by 16 weeks of additional chemotherapy, and high-risk participants receive 6 weeks of initial chemotherapy followed by additional cycles.

12-54 weeks

Radiation and/or Surgery

Participants undergo radiation therapy and/or surgical resection based on their risk group and treatment response.

Varies

Maintenance Therapy

Intermediate and high-risk participants receive maintenance therapy with anti-angiogenic chemotherapy.

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. This includes monitoring for event-free survival and incidence of toxicities.

2-5 years

Treatment Details

Interventions

• Bevacizumab
• Cyclophosphamide
• Dactinomycin
• Proton Beam Radiation
• Surgical Resection
• Vincristine

Trial Overview The study tests risk-adapted therapy using standard/intensified chemo, radiation, surgery for RMS patients. It aims to improve survival rates in intermediate/high-risk groups by adding maintenance anti-angiogenic therapy after initial treatment.

Participant Groups

Group I: Low-Risk, Subset 2 Experimental Treatment 7 Interventions

Lymph node sampling will take place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide). The tumor is evaluated to determine how it responded to treatment. Radiation therapy and/or surgical resection is performed to destroy or remove the remaining tumor. Twelve additional weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) is given, followed by evaluation for tumor response. If delayed for medical reasons, radiation therapy and/or surgical resection is done at this time. Participants then receive 16 weeks of additional chemotherapy (vincristine, dactinomycin and cyclophosphamide). No further treatment is given, and participants are observed closely. Myeloid growth factor will be given if needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Group II: Low-Risk, Subset 1 Experimental Treatment 8 Interventions

Lymph node sampling will take place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin and cyclophosphamide). They are then evaluated to determine how the tumor responded to treatment. Twelve additional weeks of chemotherapy (vincristine and dactinomycin) is given, followed by evaluation for tumor response. No further treatment is given, and participants are observed closely. Myeloid growth factor is given if needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Group III: Intermediate-Risk Experimental Treatment 10 Interventions

Lymph node sampling takes place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide). The tumor is evaluated for treatment response. Radiation therapy and/or surgical resection is done. Twelve weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) is followed by evaluation for tumor response. If delayed for medical reasons, radiation therapy and/or surgical resection is done at this time. Participants receive 16 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) followed by 12 weeks of maintenance treatment (bevacizumab, sorafenib, oral cyclophosphamide). No further treatment is given, and participants are observed closely. Myeloid growth factor is given if needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

Group IV: High-Risk Experimental Treatment 16 Interventions

Lymph node sampling takes place pretreatment and pre-surgery. Participants receive 6 weeks (2 cycles) chemotherapy (vincristine and irinotecan). The tumor is evaluated for treatment response. 3 cycles of chemotherapy \[vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide (or etoposide phosphate) (VDC/IE)\] are given. Dexrazoxane is given prior to each dose of doxorubicin. Radiation therapy begins at week 4 or 20 (depending on tumor location) while receiving vincristine and irinotecan. 2 cycles of VDC/IE, 4 cycles of modified vincristine, dactinomycin, cyclophosphamide (VAC), then 2 cycles of modified vincristine/irinotecan (total of 54 weeks). High risk participants also receive additional maintenance therapy beginning week 55 with anti-angiogenic chemotherapy (bevacizumab, sorafenib, cyclophosphamide). Myeloid growth factor is given as needed. Participants also receive \^1\^1C-methionine as described in the intervention section.

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

With modern treatments, over 70% of children and adolescents with rhabdomyosarcoma can be cured, highlighting the importance of accurate diagnosis and multidisciplinary therapy for maximizing cure rates.

Current research is focusing on new therapies, including topoisomerase-I inhibitors and molecular characterization of tumors, which may lead to more effective treatments for high-risk patients who currently have poor outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rhabdomyosarcoma: new windows of opportunity. Breitfeld, PP., Meyer, WH.[2022]

In a study using a laboratory model of childhood rhabdomyosarcoma (RMS) with seven patient-derived xenografts, the conventional chemotherapy agent vincristine was found to be the most effective treatment.

L-phenylalanine mustard (L-PAM) showed remarkable efficacy, causing complete tumor regressions in six out of seven RMS lines, including those resistant to cyclophosphamide, indicating its potential as a powerful treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Childhood rhabdomyosarcoma xenografts: responses to DNA-interacting agents and agents used in current clinical therapy. Houghton, JA., Cook, RL., Lutz, PJ., et al.[2019]

In a clinical trial involving 271 patients with low-risk embryonal rhabdomyosarcoma, a shorter treatment regimen using lower-dose cyclophosphamide and radiotherapy achieved a 3-year failure-free survival rate of 89%, indicating effective treatment without compromising outcomes.

The study demonstrated that this modified therapy resulted in significantly fewer expected treatment failures (35 observed vs. 48.4 expected), suggesting that reducing treatment duration and dosage can maintain efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Walterhouse, DO., Pappo, AS., Meza, JL., et al.[2022]

The combination of temsirolimus with standard chemotherapy (VAC/VI) in children with intermediate-risk rhabdomyosarcoma was found to be feasible and well tolerated, with only 20% of patients experiencing dose-limiting toxicities.

Out of 10 patients treated, no treatment-related deaths occurred, and the regimen is currently being evaluated for its efficacy in a phase III trial against standard chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group. Oberoi, S., Qumseya, A., Xue, W., et al.[2023]

In a clinical trial involving 92 children with rhabdomyosarcoma, both high single doses and divided doses of dactinomycin (ACT-D) combined with vincristine and cyclophosphamide showed similar effectiveness, with major response rates of 67% and 70%, respectively.

The study found that administering high, single doses of ACT-D resulted in low toxicity and did not increase adverse effects compared to the divided dosing, suggesting it is a feasible treatment option that requires less hospitalization for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor response and toxicity after single high-dose versus standard five-day divided-dose dactinomycin in childhood rhabdomyosarcoma. Carli, M., Pastore, G., Perilongo, G., et al.[2017]

References

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

Outcome and Patterns of Relapse in Childhood Parameningeal Rhabdomyosarcoma Treated With Proton Beam Therapy. [2020]

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

The Intergroup Rhabdomyosarcoma Study-I. A final report. [2019]

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

Rhabdomyosarcoma: new windows of opportunity. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Childhood rhabdomyosarcoma xenografts: responses to DNA-interacting agents and agents used in current clinical therapy. [2019]

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

Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. [2022]

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

Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group. [2023]

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

Tumor response and toxicity after single high-dose versus standard five-day divided-dose dactinomycin in childhood rhabdomyosarcoma. [2017]

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

The development of VAC chemotherapy in rhabdomyosarcoma: what does one do for an encore? [2019]

9. England pubmed.ncbi.nlm.nih.gov

Radiotherapy and adjuvant combination chemotherapy for childhood rhabdomyosarcoma. [2019]

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

Genital rhabdomyosarcoma: current management and review of the literature. [2015]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Optimal management strategies for rhabdomyosarcoma in children. [2021]