Chemotherapy for Rhabdomyosarcoma

Recruiting at 17 trial locations

Overseen By Jessica Crimella, BSN, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must be taking: Cyclophosphamide

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Active infection, Cardiac arrhythmia, 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

Duration: 12-42 weeks

28 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot be on any other cancer treatments. Alternative medications like cannabis products are allowed.

What evidence supports the effectiveness of the drugs used in the chemotherapy for rhabdomyosarcoma?

Research shows that vinorelbine, when combined with cyclophosphamide, has shown clinical activity in treating relapsed rhabdomyosarcoma. Additionally, a novel regimen including vinorelbine, ifosfamide, vincristine, and actinomycin-D demonstrated a major response in high-risk rhabdomyosarcoma patients. ^{1 2 3 4 5}

Is chemotherapy for rhabdomyosarcoma generally safe in humans?

Vinorelbine, a drug used in chemotherapy, has been studied for safety and shows a favorable safety profile with manageable side effects like neutropenia (low white blood cell count) and limited neurotoxicity. It has been tested in various cancers, including lung and breast cancer, and can be administered safely in outpatient settings. ^{6 7 8 9 10}

What makes the chemotherapy treatment for rhabdomyosarcoma unique?

This chemotherapy treatment for rhabdomyosarcoma is unique because it combines vinorelbine with low-dose cyclophosphamide, which has shown promise as a maintenance regimen for high-risk patients. Vinorelbine, a semisynthetic vinca alkaloid, has demonstrated effectiveness in relapsed cases, particularly in alveolar rhabdomyosarcoma, and is used alongside other drugs like actinomycin-D and vincristine to enhance treatment outcomes. ^{1 2 4 5 11}

What is the purpose of this trial?

This trial is testing four different chemotherapy schedules for patients with a specific type of advanced cancer. The goal is to find the best way to treat the disease by comparing different timing and combinations of chemotherapy treatments.

Research Team

Jonathan Metts, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for individuals newly diagnosed with metastatic Fusion Positive Rhabdomyosarcoma. They must have tissue available for testing, no prior chemotherapy, and molecular confirmation of PAX/FOXO1 fusion. Participants need to agree to contraception use if applicable and be able to take oral medications if in Arm B. Pregnant or breastfeeding women are excluded.

Inclusion Criteria

My cancer has spread to distant parts of my body, confirmed by tests.

I have been newly diagnosed with rhabdomyosarcoma.

I will use contraception for 4 months after my chemotherapy ends.

Exclusion Criteria

I do not have any severe illnesses or social situations that would prevent me from following the study's requirements.

Patients who are pregnant or breastfeeding are not eligible because there is no available information regarding human fetal or teratogenic toxicities. Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours of starting protocol therapy

Participants who are considered unable to comply with the safety monitoring requirements of the study are not eligible

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive chemotherapy based on chosen strategy: first strike, first strike-second strike (maintenance), adaptively timed, or conventional chemotherapy

12-42 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-5 years

Treatment Details

Interventions

• Actinomycin D
• Cyclophosphamide
• Cyclophosphamide Pill
• Vincristine
• Vinorelbine

Trial Overview The study tests four chemotherapy strategies on Rhabdomyosarcoma: a first strike therapy (Arm A), a maintenance therapy after initial treatment (Arm B), an adaptively timed therapy based on disease response (Arm C), and conventional chemotherapy (Arm D). Patients choose their treatment arm with their physician.

Participant Groups

Group I: Arm C - Adaptive Therapy Experimental Treatment 3 Interventions

Therapy with VAC that starts and stops based on response, adaptive timing of therapy, with a prolonged time to progression rather than complete remission goal

Group II: Arm B - Second Strike - Maintenance Experimental Treatment 5 Interventions

Participants will receive conventional doses of Vincristine/Actinomycin D/Cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks and then switch to up to 2 years of vinorelbine/oral cyclophoshamide

Group III: Arm A - First Strike Experimental Treatment 3 Interventions

Participants will receive 42 weeks of conventional doses of vinorelbine, actinomycin D and cyclophosphamide

Group IV: Arm - D Conventional Therapy Active Control 3 Interventions

Participants will receive a chemotherapy combination based on published trials. An example would be 42 weeks of VAC but may also include irinotecan, doxorubicin, ifosfamide, etoposide.

Actinomycin D is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Dactinomycin for:

• Rhabdomyosarcoma
• Wilms tumor
• Ewing's sarcoma

Approved in United States as Actinomycin D for:

• Rhabdomyosarcoma
• Wilms tumor
• Ewing's sarcoma
• Trophoblastic neoplasm

Approved in Canada as Dactinomycin for:

• Rhabdomyosarcoma
• Wilms tumor
• Ewing's sarcoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

National Pediatric Cancer Foundation

Collaborator

Trials

8

Recruited

300+

Findings from Research

A meta-analysis of five Phase 2 trials involving 156 patients with relapsed or refractory rhabdomyosarcoma (RMS) showed that vinorelbine significantly increased response rates in patients with alveolar rhabdomyosarcoma (ARMS) by 41% compared to those with embryonal rhabdomyosarcoma (ERMS).

Vinorelbine demonstrated efficacy as a treatment option for relapsed RMS, particularly in ARMS patients, suggesting it warrants further investigation for newly diagnosed cases, as there was no significant difference in disease progression rates between ARMS and ERMS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis. Allen-Rhoades, W., Lupo, PJ., Scheurer, ME., et al.[2023]

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]

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]

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]

The combination of cyclophosphamide, epirubicin, and vinorelbine (CEN) was administered to 56 patients with advanced breast cancer, resulting in a 50% objective response rate, with a median overall survival time of 90 weeks.

While the treatment showed acceptable tolerability, with manageable side effects like neutropenia and nausea, it did not demonstrate improved efficacy compared to other first-line treatments for advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of cyclophosphamide, epirubicin and vinorelbine in the treatment of advanced breast cancer. Esteban, E., de Sande, G., Puertas, J., et al.[2019]

Vinorelbine tartrate is an effective treatment for non-small cell lung cancer (NSCLC) and has a low reported prevalence of respiratory adverse effects, typically under 5%.

However, there is a potential risk of increased pulmonary toxicity in patients with diffuse pulmonary NSCLC, as demonstrated by a case of acute respiratory failure following vinorelbine infusion in a patient with a hypercoagulable state.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respiratory failure following vinorelbine tartrate infusion in a patient with non-small cell lung cancer. Kouroukis, C., Hings, I.[2019]

Vinorelbine tartrate is an FDA-approved treatment for advanced, unresectable non-small cell lung cancer, known for its favorable safety profile and the ability to be administered weekly in an outpatient setting.

While approximately 40% of patients experience severe granulocytopenia, this side effect is quickly reversible, and only about 8% of patients need hospitalization for related complications, indicating that it can be managed effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vinorelbine tartrate: a promising new chemotherapeutic agent. Baldwin, PD.[2018]

Vinorelbine (Navelbine) has shown significant antitumor activity in various cancers, including a 33% response rate in non-small cell lung cancer and a 53% response rate in advanced breast cancer, based on early phase II studies.

The drug primarily causes neutropenia as a side effect, with minimal neurotoxicity and manageable other side effects, making it a promising option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in vinca-alkaloids: Navelbine. Marty, M., Extra, JM., Espie, M., et al.[2018]

Vinorelbine, an oral and intravenous chemotherapy drug, was found to have a maximum tolerated dose of 30 mg/m² in children without bone marrow involvement, with myelosuppression (reduced blood cell production) being the main side effect.

The study revealed that children metabolize vinorelbine differently than adults, showing higher plasma clearance and lower overall drug exposure, which may influence dosing strategies for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I evaluation of oral and intravenous vinorelbine in pediatric cancer patients: a report from the Children's Oncology Group. Johansen, M., Kuttesch, J., Bleyer, WA., et al.[2018]

In a study of 24 pediatric patients with rhabdomyosarcoma, those treated with actinomycin-D had a higher 2-year overall survival rate (78.0%) compared to those treated with carboplatin (68.2%).

Despite the difference in survival rates, carboplatin was found to be a safe alternative to actinomycin-D, with no significant differences in hematological or non-hematological toxicities between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Replacing actinomycin-D with Carboplatin for newly diagnosed rhabdomyosarcoma. Sezgin, G., Acipayam, C., Bayram, I., et al.[2022]

References

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

Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis. [2023]

2. 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]

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

Rhabdomyosarcoma: new windows of opportunity. [2022]

4. 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]

5. Japan pubmed.ncbi.nlm.nih.gov

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

6. Netherlands pubmed.ncbi.nlm.nih.gov

A phase II trial of cyclophosphamide, epirubicin and vinorelbine in the treatment of advanced breast cancer. [2019]

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

Respiratory failure following vinorelbine tartrate infusion in a patient with non-small cell lung cancer. [2019]

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

Vinorelbine tartrate: a promising new chemotherapeutic agent. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

Advances in vinca-alkaloids: Navelbine. [2018]

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

Phase I evaluation of oral and intravenous vinorelbine in pediatric cancer patients: a report from the Children's Oncology Group. [2018]

11. Thailand pubmed.ncbi.nlm.nih.gov

Replacing actinomycin-D with Carboplatin for newly diagnosed rhabdomyosarcoma. [2022]