Combination Chemotherapy for Rhabdomyosarcoma

Not currently recruiting at 280 trial locations

Overseen By Jessica C. Hochberg

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of chemotherapy drugs to determine their effectiveness in treating high-risk rhabdomyosarcoma, a cancer that often recurs or spreads after treatment. The trial examines whether adding vinorelbine (a chemotherapy medication) to the standard treatment—vincristine, dactinomycin (also known as Actinomycin D or Cosmegen), and cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan)—can better control or eliminate the cancer. Individuals recently diagnosed with rhabdomyosarcoma that is likely to spread or recur might be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

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.

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

Studies have shown that the treatments in this trial—vinorelbine, vincristine, dactinomycin, and cyclophosphamide—are generally well-tolerated by patients with rhabdomyosarcoma. Research indicates that vinorelbine, when used in patients with high-risk rhabdomyosarcoma, allows most to receive over 80% of the planned doses without severe side effects, suggesting it is manageable for many patients.

Cyclophosphamide, another important drug in this trial, has undergone extensive study. It is effective but can cause side effects if not dosed properly. However, patients receiving higher doses have shown better survival rates, indicating its benefits can outweigh the risks when managed carefully.

Dactinomycin is also part of the treatment. Although highly toxic, it must be handled with care. Despite this, it has been safely used in children with cancers similar to rhabdomyosarcoma, with its safety and effectiveness well-documented.

This trial is in a late phase (Phase 3), meaning previous studies have already examined these drugs' safety and effectiveness in humans. The treatments have been found safe enough to be tested in larger groups of patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination chemotherapy treatments for rhabdomyosarcoma because they integrate several potent chemotherapy drugs—Cyclophosphamide, Dactinomycin, and Vinorelbine Tartrate—into a carefully timed regimen. Unlike other treatments that might focus on a single drug or a different combination, this approach uses a multi-pronged attack to target cancer cells more effectively. The inclusion of Vinorelbine Tartrate is particularly notable, as it adds a unique mechanism to the mix, potentially improving outcomes by disrupting cancer cell division in a novel way. Additionally, the treatment protocol incorporates radiation therapy and regular imaging and biopsies to closely monitor progress, ensuring a comprehensive approach to combatting this aggressive cancer.

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

This trial will compare two treatment arms for high-risk rhabdomyosarcoma. Arm A includes the VAC regimen (vincristine, dactinomycin, and cyclophosphamide), while Arm B adds vinorelbine to the VAC regimen. Research has shown that adding vinorelbine to the current VAC treatment plan may improve results for patients with high-risk rhabdomyosarcoma. A review of several studies found a 41% increase in response rates when vinorelbine was used for relapsed or difficult-to-treat rhabdomyosarcoma. Other studies suggest that using continuous low doses of cyclophosphamide with vinorelbine can greatly improve patient outcomes. Cyclophosphamide and dactinomycin damage the DNA of cancer cells, aiding in their destruction. The combination of these drugs aims to stop cancer cells from growing and spreading, offering hope for better long-term control of the disease. ^{2 3 4 6 7}

Who Is on the Research Team?

Wendy Allen-Rhoades

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S036030161834046X

Worse Outcomes for Head and Neck Rhabdomyosarcoma ... Cumulative cyclophosphamide dose was significantly associated with 2-year LF: 0% for cumulative dose of >20 g/m2 versus 15.3% for ≤20 g/m2 (P = .04). In ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30508617/

Worse Outcomes for Head and Neck Rhabdomyosarcoma ... There was a trend toward worse event-free survival for parameningeal RMS patients who received reduced-dose-intensity cyclophosphamide (59.2% vs 70.6%, P = .11 ...

3. ascopubs.org ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.10092

Clinical outcomes in adult and childhood ... 10092 Background: The outcomes for the patients (pts) with adult RMS have remained poor, with approximately 30% at 5-year survival.

4. mdpi.com mdpi.com/2072-6694/14/9/2270

Optimizing Rhabdomyosarcoma Treatment in Adolescents ... Although group III patients with an unfavorable tumor site showed little improvement in outcomes after treatment with dose-escalated cyclophosphamide, this ...

5. redjournal.org redjournal.org/article/S0360-3016(18)34046-X/abstract

Worse Outcomes for Head and Neck Rhabdomyosarcoma ... 24). Patients treated with protons were more likely to have received reduced-dose cyclophosphamide (P < .0001). The 2-year LF was 7.9% in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6441953/

Worse Outcomes for Head and Neck Rhabdomyosarcoma ... Patients treated with protons were more likely to have received reduced-dose cyclophosphamide (p<0.0001). The 2-year LF was 7.9% in the IMRT cohort versus 14.6% ...

7. cancertherapyadvisor.com cancertherapyadvisor.com/news/cyclophosphamide-reduction-in-rhabdomyosarcoma/

Cyclophosphamide Reduction in Rhabdomyosarcoma For patients who received a higher dose of cyclophosphamide, the 3-year failure-free survival rate was 83%. The authors noted that the results ...