International PPB/DICER1 Registry

Study Overview
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Brief Summary
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Pleuropulmonary blastoma (PPB) is a rare malignant neoplasm of the lung presenting in early childhood. Type I PPB is a purely cystic lesion, Type II is a partially cystic, partially solid tumor, Type III is a completely solid tumor. Treatment of children with PPB is at the discretion of the treating institution. This study builds off of the 2009 study and will also seek to enroll individuals with DICER1-associated conditions, some of whom may present only with the DICER1 gene mutation, which will help the Registry understand how these tumors and conditions develop, their clinical course and the most effective treatments.

Detailed Description
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PPB is a rare cancer of the lung presenting in early childhood, mostly commonly from birth to age  72 months. PPB occurs within the lung or between the lung and the chest wall. There are three primary forms of PPB called Types I, II, and III PPB. PPB is related to an underlying change/mutation in a gene called DICER1 which impacts gene expression and cell growth. DICER1 mutations may also lead to the development of other tumors in children and adults. The International PPB/DICER1 Registry offers information based on previous data from Registry participants and the medical literature and collaborative efforts with international rare tumor groups. Retrospective and real-time central pathology review is encouraged. Therapy decisions remain at the discretion of the treating institution. Children with Type I PPB require surgery and sometimes chemotherapy. Therapy decisions are the responsibility of the treating institution. Surgical guidelines are presented. It is unknown whether adjuvant chemotherapy improves cure rates for Type I PPB patients. Chemotherapy options include a 22-week regimen: 4 courses of vincristine, actinomycin D and cyclophosphamide (VAC) followed by 3 courses of vincristine and actinomycin D (VA). Children with Types II and III PPB, require surgery, chemotherapy and sometimes radiation therapy. Many children with Types II or III PPB receive a single-arm multi-agent chemotherapy neo-adjuvant/adjuvant regimen of IVADo (ifosfamide, vincristine, actinomycin, doxorubicin) for 36 weeks. Second and possible 3rd look surgery may be considered for local control. Radiation therapy may be considered.

Official Title
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International Pleuropulmonary Blastoma/DICER1 Registry (for PPB, DICER1 and Associated Conditions)

Conditions
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Pleuropulmonary Blastoma, Sertoli-Leydig Cell Tumor, DICER1 Syndrome, Cystic Nephroma, Wilms Tumor, Pineoblastoma, Renal Sarcoma, Nodular Hyperplasia of Thyroid, Nasal Chondromesenchymal Hamartoma, Ciliary Body Medulloepithelioma, Neuroblastoma, Pituitary Cancer, Embryonal Rhabdomyosarcoma, Ovarian Sarcoma, Gynandroblastoma

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Known or suspected PPB or related thoracic tumor Known or suspected sex-cord stromal tumor including Sertoli-Leydig cell tumor and gynandroblastoma (males or females) Other known or suspected DICER1-related condition including ovarian sarcoma, cystic nephroma, renal sarcoma, pineoblastoma, pituitary blastoma, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma and others Individuals with known or suspected DICER1 pathogenic variation regardless of whether they have an established DICER1-associated condition Informed consent by patient/ or parent/guardian (also, where appropriate: assent and HIPAA consent) Exclusion criteria: Absence of appropriate consent for Registry participation
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Type I PPB<br>Type I PPB is an early manifestation of this malignant disease, cured in some cases by surgery. Surgical guidelines are presented. It is unknown whether adjuvant chemotherapy improves cure rates for individuals with Type I PPB. If the treating physicians select adjuvant chemotherapy treatment, chemotherapy options include a 22-week regimen: 4 courses of vincristine, actinomycin D and cyclophosphamide (VAC) followed by 3 courses of vincristine and actinomycin D (VA). Therapy decisions are the responsibility of the treating institution. | |
| Types II and III PPB<br>Types II and III PPB are aggressive sarcomas. Surgery and chemotherapy are necessary in all cases. Surgical guidelines are presented. Many children with Types II or III PPB receive a single-arm multi-agent chemotherapy neo-adjuvant/adjuvant regimen of IVADo (ifosfamide, vincristine, actinomycin, doxorubicin) for 36 weeks. Second and possible 3rd look surgery may be considered for local control. Radiation therapy may be considered. Specific therapy decisions are the responsibility of the treating institution. | |
| Type Ir PPB<br>Type Ir (regressed) PPB is a unique, purely cystic tumor which lacks a primitive cell component. The International PPB/DICER1 Registry will enroll and follow participants with Type Ir PPB, regardless of age. | |
| DICER1 Gene or Cond Assoc with DICER1<br>PPB and the associated conditions found in PPB families suggest a familial tendency to formation of tumors. The International PPB/DICER1 Registry for PPB, DICER1 and Associated Conditions study will enroll and follow participants who have the DICER1 gene mutations or conditions associated with PPB or DICER1. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | The primary endpoint for statistical analysis will be time from start treatment to an event, defined as the occurrence of progression or recurrence of PPB, occurrence of a second malignant neoplasm, or death from any cause that is at least possibly related to the original disease or treatment. | 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response to chemotherapy | The investigators will assess overall response to chemotherapy among participants with radiographically measurable tumor following initial surgery or biopsy. | 7 years | 
| Overall survival | The investigators will assess overall survival and time to death from any cause among participants. | 7 years | 
| Quality of life outcomes in individuals diagnosed with PPB. | Chemotherapy and surgery may have adverse effects on the quality of life outcomes. Multiple factors may impact quality of life for participants.This study will allow the investigators to assess the quality of life outcomes in participants with DICER1-related tumors and will compare outcomes to those with more common childhood cancers. | 7 years | 
| Cardiac outcomes in individuals diagnosed with PPB. | Chemotherapy and surgery may have adverse effects on cardiac outcomes. This study will allow the investigators to assess the cardiac outcomes as measured by ejection fraction and shortening fraction via echocardiogram of participants with DICER1-related tumors, and compare outcomes to those with more common childhood cancers. | 7 years | 
| Pulmonary function testing results in individuals diagnosed with PPB | Chemotherapy and surgery may have adverse effects on pulmonary outcomes. This study will allow the investigators to assess the pulmonary outcome of participants as ascertained by pulmonary function testing (forced vital capacity (FVC), FEV1(forced expiratory volume in 1 second)/FVC) with DICER1-related tumors, and compare outcomes to those with more common childhood cancers. | 7 years | 
| Incidence of neoplasms in individuals with DICER1-related conditions or germline DICER1 variants. mutation. | This protocol will include individuals with germline DICER1 mutations and will calculate incidence rates of specific neoplasms in this population | 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pleuropulmonary blastoma, PPB, DICER1, Sertoli-Leydig cell tumor, cystic nephroma