Combination Chemotherapy for Rhabdomyosarcoma

Recruiting at 268 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: CYP3A4 inhibitors, inducers

Disqualifiers: Uncontrolled infection, CNS involvement, 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: 52

Duration: 42 weeks

118 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial compares the safety and effect of adding vinorelbine to vincristine, dactinomycin, and cyclophosphamide (VAC) for the treatment of patients with high risk rhabdomyosarcoma (RMS). High risk refers to cancer that is likely to recur (come back) after treatment or spread to other parts of the body. This study will also examine if adding maintenance therapy after VAC therapy, with or without vinorelbine, will help get rid of the cancer and/or lower the chance that the cancer comes back. Vinorelbine and vincristine are in a class of medications called vinca alkaloids. They work by stopping cancer cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Vinorelbine, vincristine, dactinomycin and cyclophosphamide are chemotherapy medications that work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial may have the potential to eliminate rhabdomyosarcoma for a long time or for the rest of patient's life.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot have taken certain drugs that affect liver enzymes (CYP3A4 inhibitors and inducers) within 7 days before joining. If you're on chemotherapy for non-cancer conditions, you must stop it before starting the trial.

What data supports the effectiveness of the drug combination used in the clinical trial for rhabdomyosarcoma?

Research shows that the combination of vinorelbine and low-dose cyclophosphamide has been used successfully in treating pediatric sarcomas, and the VAC regimen (vincristine, dactinomycin, and cyclophosphamide) has shown improved survival rates in low-risk rhabdomyosarcoma patients. Additionally, the VIVA regimen, which includes vinorelbine, has demonstrated significant responses in high-risk rhabdomyosarcoma patients. ^{1 2 3 4 5}

Is the combination chemotherapy for rhabdomyosarcoma safe for humans?

The combination chemotherapy for rhabdomyosarcoma, which includes drugs like cyclophosphamide, dactinomycin, and vinorelbine, has been studied in various trials. While patients often experience some side effects like hematological toxicity (blood-related side effects), major complications are rare, and the treatment is generally considered feasible and safe for use in humans. ^{1 3 4 5 6}

What makes the combination chemotherapy for rhabdomyosarcoma unique?

This treatment is unique because it combines vinorelbine with low-dose cyclophosphamide, which is being explored as a maintenance regimen for high-risk patients, offering a potentially new approach compared to traditional therapies that often use higher doses or different drug combinations. ^{1 3 7 8 9}

Research Team

Wendy Allen-Rhoades

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients up to 50 years old with high-risk rhabdomyosarcoma (RMS), including embryonal and alveolar types, but not adult-type pleomorphic. Eligible participants must have newly diagnosed RMS, meet specific stage and group criteria, have a certain kidney function level, normal bilirubin levels unless obstructed by tumor, and provide informed consent. Pregnant or breastfeeding women are excluded as well as those with uncontrolled infections or central nervous system involvement of RMS.

Inclusion Criteria

My kidney function is normal or near normal.

I am 50 years old or younger.

My FOXO1 fusion status will be checked by the 4th week of treatment.

Exclusion Criteria

I haven't taken strong medication affecting liver enzymes in the last week.

My cancer has spread to my brain or spinal cord.

I have not had chemotherapy or radiation for RMS before joining.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive chemotherapy with vincristine, dactinomycin, and cyclophosphamide (VAC) or vinorelbine, dactinomycin, and cyclophosphamide (VINO-AC) for up to 14 cycles, with radiation therapy on weeks 13 and 40

42 weeks

Every 21 days for up to 14 cycles

Maintenance

Patients receive maintenance therapy with vinorelbine and oral cyclophosphamide for up to 6 cycles

24 weeks

Every 28 days for up to 6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3 months for year 1, every 4 months for years 2-3, and every 6 months for years 4-5

Treatment Details

Interventions

• Cyclophosphamide
• Dactinomycin
• Vinorelbine Tartrate

Trial Overview The study tests the addition of vinorelbine to standard chemotherapy (vincristine, dactinomycin, cyclophosphamide) in treating high-risk RMS. It also examines maintenance therapy post-chemotherapy to see if it helps eliminate cancer or prevent its return. The medications used aim to stop cancer cell growth by damaging their DNA.

Participant Groups

Group I: Arm B (vinorelbine, VAC, VINO-CPO) Experimental Treatment 13 Interventions

Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes or IVP over 1-5 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40. MAINTENANCE: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide PO on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients in both arms undergo CT, MRI, PET, x-ray imaging, and/or bone scan, as well as blood sample collection throughout the trial. Patients may also undergo bone marrow aspiration and/or biopsy as clinically indicated.

Group II: Arm A (VAC, VINO-CPO) Experimental Treatment 13 Interventions

Patients receive vincristine sulfate IV on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 5, 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes or IVP over 1-5 minutes on day 1 of cycles 1-5, 8-10, and 11-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40. MAINTENANCE: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide PO on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients in both arms undergo CT, MRI, PET, x-ray imaging, and/or bone scan, as well as blood sample collection throughout the trial. Patients may also undergo bone marrow aspiration and/or biopsy as clinically indicated.

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

The pilot study involving 18 patients aged 2-23 years demonstrated that the combination of vinorelbine and low-dose cyclophosphamide is feasible and shows activity against recurrent sarcomas, with one complete remission and six partial remissions observed.

Vinorelbine at a dose of 25 mg/m2 resulted in manageable toxicity, with 37% of cycles showing Grade 3 or higher neutropenia, while the recommended maintenance doses for future trials are cyclophosphamide 25 mg/m2 daily and vinorelbine 25 mg/m2 on specific days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Casanova, M., Ferrari, A., Bisogno, G., et al.[2018]

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]

The novel chemotherapy regimen, which includes vinorelbine with the VIVA combination, was feasible and led to a major response in all four patients with high-risk rhabdomyosarcoma after three cycles.

Despite significant hematological toxicity, there were no major complications or neurotoxicity, and all patients remained alive after a median follow-up of 11 months from diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VIVA (vinorelbine, ifosfamide, vincristine, actinomycin-D): A new regimen in the armamentarium of systemic therapy for high-risk rhabdomyosarcoma. Ferrari, A., Chiaravalli, S., Zecca, M., et al.[2021]

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]

An 11-month-old boy with rhabdomyosarcoma resistant to standard chemotherapy (vincristine, actinomycin-D, cyclophosphamide, and adriamycin) achieved complete remission after receiving a new combination therapy of vinblastine, cis-platinum, and bleomycin (VPB therapy).

The VPB therapy not only effectively reduced the tumor size but also did so without causing severe adverse effects, indicating its potential as a safe and effective treatment option for resistant rhabdomyosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rhabdomyosarcoma of the urinary bladder: complete remission induced by vinblastine, cis-platinum, and bleomycin]. Tawa, A., Yabuta, R., Yuumura, K., et al.[2013]

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]

References

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

Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. [2018]

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

Rhabdomyosarcoma: new windows of opportunity. [2022]

3. 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]

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

VIVA (vinorelbine, ifosfamide, vincristine, actinomycin-D): A new regimen in the armamentarium of systemic therapy for high-risk rhabdomyosarcoma. [2021]

5. 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]

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

Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. [2021]

7. Japan pubmed.ncbi.nlm.nih.gov

[Rhabdomyosarcoma of the urinary bladder: complete remission induced by vinblastine, cis-platinum, and bleomycin]. [2013]

8. England pubmed.ncbi.nlm.nih.gov

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

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

Treatment of adult rhabdomyosarcoma. [2022]