Chemotherapy for Rhabdomyosarcoma

Recruiting at 166 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

Trial Summary

What is the purpose of this trial?

This trial uses chemotherapy drugs to treat patients with very low-risk and low-risk rhabdomyosarcoma. The goal is to maintain good outcomes while reducing treatment intensity. The study also examines if patients with specific DNA mutations benefit from more intensive therapy.

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.

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

Research shows that more than 70% of children and adolescents with rhabdomyosarcoma are cured with modern treatments, including the combination of vincristine, dactinomycin, and cyclophosphamide. Studies also confirm that this combination is effective, with major responses observed in 67% to 70% of patients, and it is feasible with low toxic effects. ^{1 2 3 4 5}

Is chemotherapy for rhabdomyosarcoma safe for humans?

The chemotherapy drugs vincristine, dactinomycin, and cyclophosphamide have been used in treating rhabdomyosarcoma and other conditions, showing low toxic effects in studies. These drugs are generally considered safe for humans, with no increased toxicity observed in certain dosing regimens. ^{1 3 4 6 7}

How is the drug combination of Cyclophosphamide, Dactinomycin, and Vincristine unique for treating rhabdomyosarcoma?

This drug combination is unique because it uses a shorter-duration therapy with lower doses of cyclophosphamide, aiming to maintain effectiveness while reducing treatment length and potential side effects for low-risk rhabdomyosarcoma patients. ^{1 2 3 4 8}

Research Team

Josephine H Haduong

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment)

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

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

Treatment Details

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.

Participant Groups

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+

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 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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Rhabdomyosarcoma: new windows of opportunity. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. 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]

5. Ireland pubmed.ncbi.nlm.nih.gov

PAX3-FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis. [2021]

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

Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group. [2023]

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

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