Chemotherapy for Rhabdomyosarcoma

Recruiting at 189 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: CYP3A4 inhibitors, inducers

Disqualifiers: Prior chemotherapy, radiation, uncontrolled infection, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 21

Duration: 24 weeks

205 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests treatments for rhabdomyosarcoma, a cancer affecting soft tissues, to determine if less intense therapy can still yield excellent outcomes in patients with very low-risk cancer. It also seeks to enhance treatment strategies for patients with genetic mutations influencing their cancer. Eligible participants are those newly diagnosed with this cancer who have not received chemotherapy or radiation. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking cancer treatments.

Will I have to stop taking my current medications?

The trial requires that you stop taking any drugs that are moderate to strong inhibitors or inducers of CYP3A4 (a liver enzyme) at least 7 days before enrolling. If you are on chemotherapy for non-cancer conditions, you must stop it before starting the trial treatment.

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

Research shows that vincristine and dactinomycin, two drugs used to treat rhabdomyosarcoma, are generally well-tolerated. In past studies with patients at very low risk for this cancer, these drugs caused some manageable side effects. Common side effects include neutropenia, a drop in white blood cells that fight infection, and anemia, a low count of red blood cells. These effects are typical and often expected with chemotherapy.

Cyclophosphamide, another drug used in treatment, is common in various cancer therapies. It can cause similar side effects, such as neutropenia and anemia, as well as nausea and hair loss. Trials closely monitor these side effects to ensure patient safety.

Overall, these treatments have been tested in many previous studies. While they have side effects, they are considered safe enough for clinical trials. Trials carefully monitor patients for any serious issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for rhabdomyosarcoma because they explore a tailored approach based on genetic mutations, which is a step beyond the current standard treatments like vincristine, dactinomycin, and cyclophosphamide, typically given in fixed regimens. These investigational treatments adapt based on the presence of MYOD1 or TP53 mutations, potentially enhancing effectiveness by personalizing therapy. Additionally, the study includes a regimen that integrates radiation therapy strategically, which could improve outcomes for patients with specific tumor profiles. This personalized approach may offer a more targeted and potentially more effective treatment for patients with rhabdomyosarcoma compared to the traditional, one-size-fits-all method.

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

Research has shown that the drugs vincristine and dactinomycin, used in a treatment plan called Regimen VA, successfully help patients with very low-risk rhabdomyosarcoma (VLR RMS). Studies have found that 83% of patients treated with this combination remain free from disease recurrence for at least five years. In this trial, patients with low-risk rhabdomyosarcoma (LR RMS) will receive a treatment plan called Regimen VAC/VA, which adds a third drug, cyclophosphamide, to form the VAC combination. Previous trials demonstrated that this approach improves survival rates, establishing it as a standard treatment for low-risk rhabdomyosarcoma. For patients with certain DNA changes, this trial includes Regimen M, offering a more intensive treatment that aims to be more effective by tailoring therapy based on genetic information. These treatments have a strong history of managing and improving outcomes for rhabdomyosarcoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Josephine H Haduong

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for patients up to 21 years old with newly diagnosed very low-risk or low-risk rhabdomyosarcoma, a type of soft tissue cancer. They must have specific stages and groups of the disease, proper organ function, no prior cancer treatments except surgery, and not be on certain drugs that affect vincristine.

Inclusion Criteria

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

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

My cancer's stage and group will be assessed.

Exclusion Criteria

I've had chemo or radiation for a non-cancer condition but will stop before starting the trial.

I've had chemotherapy or radiation before for cancer, but surgery was only for removing it.

I am currently pregnant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive chemotherapy with vincristine and dactinomycin for VLR RMS or vincristine, dactinomycin, and cyclophosphamide for LR RMS. Treatment is adjusted based on mutation status.

24 weeks

Visits every 21 days for 8 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Regimen M

Patients with positive mutation status receive intensified therapy with vincristine, dactinomycin, and cyclophosphamide, potentially including radiation therapy.

12-13 cycles

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Dactinomycin
• Vincristine

Trial Overview The study tests a chemotherapy regimen using vincristine and dactinomycin over 24 weeks for very low-risk patients. It also assesses standard chemo effectiveness in low-risk patients and intensifies therapy for those with DNA mutations to improve outcomes.

How Is the Trial Designed?

Group I: Regimen VAC/VA (VL RMS) Experimental Treatment 8 Interventions

Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Radiation therapy (if needed) will be administered at cycle 5.Patients undergo CT scan, MRI, bone scan, PET scan and tumor biopsy throughout the study.

Group II: Regimen VA (VLR RMS) Experimental Treatment 6 Interventions

Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Patients undergo CT scan, MRI, bone scan, PET scan and tumor biopsy throughout the study.

Group III: Regimen M (positive mutation) Experimental Treatment 9 Interventions

Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5. Patients undergo CT scan, MRI, bone scan, PET scan and tumor biopsy throughout the study.

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?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 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]

Postoperative irradiation of the tumor bed is unnecessary when patients receive a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) for 2 years after excision of localized rhabdomyosarcoma, as shown in a study of 780 patients.

Intensive chemotherapy regimens, including pulse VAC or VAC combined with adriamycin, were effective in advanced stages of rhabdomyosarcoma, achieving tumor regression in 85% of patients with gross residual disease and 68-74% in those with metastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Intergroup Rhabdomyosarcoma Study: update, november 1978. Maurer, HM.[2007]

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]

The study compared two chemotherapy regimens for treating intermediate risk rhabdomyosarcoma, finding that while both had similar clinical outcomes, the mean direct medical costs were significantly different: $164,757 for VAC and $102,303 for VAC/VI.

Neither treatment was clearly more cost-effective, but costs varied greatly based on pharmaceutical pricing and treatment location, highlighting the impact of rising drug prices on healthcare expenses, which increased costs by 15% to 20% beyond clinical trial pricing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group. Russell, HV., Chi, YY., Okcu, MF., et al.[2023]

Camptothecin has been identified as a selective inhibitor for alveolar rhabdomyosarcoma (ARMS), showing greater effectiveness in inhibiting cell growth and inducing cell death in ARMS cells compared to embryonal rhabdomyosarcoma (ERMS) cells.

The sensitivity of ARMS cells to camptothecin is linked to the presence of the PAX3-FKHR fusion protein, which enhances the drug's effectiveness, suggesting that targeting this pathway could lead to more effective treatments for ARMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PAX3-FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis. Zeng, FY., Cui, J., Liu, L., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05304585

Study Details | NCT05304585 | Chemotherapy for the ... This phase III trial aims to maintain excellent outcomes in patients with very low risk rhabdomyosarcoma (VLR-RMS) while decreasing the burden of therapy.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10931395/

Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS ... Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A ...

3. ufhealth.org ufhealth.org/clinical-trials/chemotherapy-for-the-treatment-of-patients-with-newly-diagnosed-very-low-risk-and-low-risk-fusion-ne

Chemotherapy for the Treatment of Patients With Newly ... This phase III trial aims to maintain excellent outcomes in patients with very low risk rhabdomyosarcoma (VLR-RMS) while decreasing the burden of therapy using ...

4. georgiacancerinfo.org georgiacancerinfo.org/clinical-trials/detail/5417

Chemotherapy for the Treatment of Patients with Newly ... III. To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutations treated with intensified therapy. OUTLINE: Patients are assigned to 1 ...

5. withpower.com withpower.com/trial/phase-3-rhabdomyosarcoma-embryonal-5-2022-1a175

Chemotherapy for Rhabdomyosarcoma What data supports the effectiveness of the drug combination of Cyclophosphamide, Dactinomycin, and Vincristine for treating rhabdomyosarcoma? Research ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2773476/

Vincristine, Actinomycin, and Cyclophosphamide Compared ... The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00075582

Study Details | NCT00075582 | Vincristine, Dactinomycin, ... Determine the failure-free survival of patients with newly diagnosed low-risk rhabdomyosarcoma treated with vincristine (V), dactinomycin (A), cyclophosphamide ...

8. asco.org asco.org/abstracts-presentations/ABSTRACT81190

Feasibility of vincristine, dactinomycin, and ... In the induction phase (total 168 cycles), the following adverse events were observed: grade 4 neutropenia (77.4%), grade 3/4 anemia (45.8%), grade 4 ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6946342/

Phase II study of vincristine, actinomycin-D ... - PubMed Central The objective of this clinical trial is to assess the efficacy and safety of alternating use of VAC 1.2 treatment (vincristine, actinomycin D, ...

10. ascopubs.org ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.10004

Vincristine, dactinomycin, cyclophosphamide (VAC) versus ... The addition of VI to VAC did not significantly improve EFS or OS compared to VAC alone for IRRMS. The lower rate of hematologic toxicity and cumulative C dose ...