Chemotherapy + Surgery for Pleuropulmonary Blastoma

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospitals and Clinics of Minnesota

Disqualifiers: Inability to consent, others

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

Compensation: Varies

Number of Visits: Unknown

156 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, prior corticosteroid therapy is allowed, so you may be able to continue some medications.

What data supports the effectiveness of the chemotherapy drugs used in the treatment of pleuropulmonary blastoma?

Research shows that combination chemotherapy, including drugs like vincristine, actinomycin-D, cyclophosphamide, and adriamycin, has been effective in treating pleuropulmonary blastoma in children, leading to tumor shrinkage and allowing for successful surgical removal. ^{1 2 3 4 5}

Is the chemotherapy treatment generally safe for humans?

Doxorubicin, a key drug in this treatment, is effective against cancer but can cause heart damage, which limits its use. Some studies focus on reducing this heart risk, but it remains a significant concern. ^{6 7 8 9 10}

What makes the chemotherapy treatment for Pleuropulmonary Blastoma unique?

This treatment combines multiple chemotherapy drugs, including doxorubicin, which is known for its effectiveness but also its potential heart-related side effects. The use of dexrazoxane (ICRF-187) alongside doxorubicin can help protect the heart from damage, making this combination potentially safer for patients. ^{11 12 13 14 15}

What is the purpose of this trial?

Pleuropulmonary Blastoma (PPB) is very rare and there is no established "standard" or "best" therapy. For many years, children with PPB around the world have been treated according to decisions made case-by-case in many different hospitals by many different physicians. No treatment has been tested in a large group of PPB patients. The goal is to treat many children with one treatment program and to learn the results of the treatment.

Research Team

Kris Ann Schultz, MD

Principal Investigator

Children's Hospitals and Clinics of Minnesota

Eligibility Criteria

This trial is for children and young adults up to 21 years old with a rare lung tumor called Pleuropulmonary Blastoma (PPB). It includes those newly diagnosed, or with prior PPB, confirmed by central pathology review. Patients must be able to give consent through a guardian and may have had previous corticosteroid therapy.

Inclusion Criteria

Diagnostic pathology for cases of diseases associated with PPB will also require registry central pathology review

If you have PPB Type I, you can participate in the study.

I have a DICER1-related condition and a DICER1 gene mutation.

Exclusion Criteria

I am unable to understand or give consent for treatment.

You have had central pathology review ruling out a diagnosis of pleuropulmonary blastoma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Surgery

Surgery is necessary for all types of PPB. For Type I, surgery is followed by optional chemotherapy. For Types II and III, surgery is followed by chemotherapy and possibly radiation therapy.

Chemotherapy

For Type I, optional chemotherapy with Vincristine, Dactinomycin, Cyclophosphamide (VAC) may be used. For Types II and III, combination chemotherapy with Ifosfamide, Vincristine, Dactinomycin, and Doxorubicin (IVADo) is recommended.

Radiation Therapy

Radiation therapy is recommended only for residual disease after maximum surgery in Types II and III PPB.

Follow-up

Participants are monitored for overall response to chemotherapy and survival, with a primary focus on event-free survival over a 5-year period.

5 years

Treatment Details

Interventions

• Cyclophosphamide
• Dactinomycin
• Doxorubicin
• Ifosfamide
• Vincristine

Trial Overview The trial tests a treatment program using drugs like Doxorubicin, Vincristine, Dactinomycin, Cyclophosphamide, and Ifosfamide on many patients to determine the effectiveness against PPB since there's no standard treatment due to its rarity.

Participant Groups

Group I: Types II and III PPB therapy Experimental Treatment 5 Interventions

Combination chemotherapy with Ifosfamide, Vincristine, Dactinomycin and Doxorubicin ("IVADo"). Second look and possible 3rd look surgery may be required. Radiation therapy is recommended only for residual disease after maximum surgery.

Group II: Type I PPB therapy Experimental Treatment 3 Interventions

PPB Type I therapy: All patients will be treated with surgery. Chemotherapy after surgery is per the treating physician(s) discretion. If chemotherapy is used the Registry will suggest that it be combination chemotherapy with Vincristine, Dactinomycin, Cyclophosphamide (VAC).

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 Hospitals and Clinics of Minnesota

Lead Sponsor

Trials

67

Recruited

5,022,000+

Findings from Research

Naringin (NR) demonstrated significant cardioprotective effects against doxorubicin (Dox)-induced cardiac toxicity in male Wistar rats, as shown by improved oxidative stress markers and mitochondrial function after NR treatment.

The study suggests that combining NR with Dox could enhance the safety of Dox chemotherapy by mitigating its harmful effects on the heart, making it a potential adjunct therapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. Kwatra, M., Kumar, V., Jangra, A., et al.[2022]

Caelyx/Doxil, a pegylated liposomal formulation of doxorubicin, has a unique pharmacokinetic profile that allows it to effectively target tumor sites while reducing toxicity compared to traditional doxorubicin.

It has been approved by the FDA and EMEA for treating AIDS-related Kaposi's sarcoma and recurrent epithelial ovarian cancer, and is being investigated for use in various other cancers, indicating its potential as a versatile treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer. Tejada-Berges, T., Granai, CO., Gordinier, M., et al.[2022]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

References

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

An aggressive childhood tumor mimicking pleural empyema: pleuropulmonary blastoma. [2011]

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

Role of chemotherapy in pediatric pulmonary blastoma. [2019]

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

Pulmonary blastoma. Case report and literature review of chemotherapy experience. [2019]

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

Case report: pulmonary blastoma in children--response to chemotherapy. [2015]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Aggressive multimodal treatment of pleuropulmonary blastoma. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

The Comparison of Biodistribution, Efficacy and Toxicity of Two PEGylated Liposomal Doxorubicin Formulations in Mice Bearing C-26 Colon Carcinoma: a Preclinical Study. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. [2022]

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

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer. [2022]

9. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-κB signaling pathways. [2020]

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

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. [2019]

12. Portugal pubmed.ncbi.nlm.nih.gov

CHEMOTHERAPY HAZARDS: ANTHRACYCLINE EXTRAVASATION INTO PLEURAL SPACE. [2022]

13. Greece pubmed.ncbi.nlm.nih.gov

Response to doxorubicin and cyclophosphamide of a human pleural mesothelioma clinically and as a xenograft in nude rats. [2013]

14. Egypt pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Hyperthermic Intrathoracic Chemotherapy following Pleurectomy and Decortication. [2021]

15. England pubmed.ncbi.nlm.nih.gov

Lethal and sublethal effects of the combination of doxorubicin and the bisdioxopiperazine, (+)-1,2,-bis (3-5-dioxopiperazinyl-1-yl) propane (ICRF 187), on murine sarcoma S180 in vitro. [2019]