2348 - Prospective Treatment of Types I, II, and III Pleuropulmonary Blastoma (PPB): A COG Groupwide Phase 3 Study (ARAR2331)
Presenter(s)
J. T. Lucas Jr1, M. Krasin2, C. E. Hill-Kayser3, J. Piao4, J. Jarzembowski5, J. Pogoriler6, D. Olson7, R. P. Guillerman8, C. C. Chen2, A. Rangaswami9, J. Rosenblum10, P. J. Schoettler11, J. Kamihara12, E. Christison-Lagay13, K. Maxa14, A. Flynn15, A. Ross16, W. Pendleton17, D. Koach17, T. Laetsch18, and K. A. P. Schultz7; 1Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, 2St. Jude Children's Research Hospital, Memphis, TN, 3Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, 4University of Southern California, Los Angeles, CA, 5Children's Hospital of Wisconsin, Milwaukee, WI, 6Children's Hospital of Philadelphia, Philadelphia, PA, 7Children's Minnesota, Minneapolis, MN, 8Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 9UCSF Medical Center-Mission Bay, San Francisco, CA, 10New York Medical College, Valhalla, NY, 11Department of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, 12Dana-Farber/Harvard Cancer Center, Boston, MA, 13Yale University, New Haven, CT, 14Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 15Children's Mercy Hospitals and Clinics, Kansas City, MO, 16Dayton Children's Hospital, Dayton, OH, 17Children's Oncology Group, Monrovia, CA, 18Division of Oncology, Children's Hospital of Philadelphia and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
Purpose/Objective(s): Pleuropulmonary blastoma (PPB) is the most common malignant lung tumor of infancy and childhood, characterized by biallelic alterations in DICER1. It progresses through distinct histopathologic types: purely cystic (Type I), mixed (Type II), and solid sarcoma (Type III). Despite intensive chemotherapy, 3-year event-free survival rates remain poor for advanced disease (66.2% for Type II; 56.1% for Type III), with local recurrence within the thorax being the most common first failure event. Preclinical and early clinical data support the use of camptothecins, specifically topotecan, due to its activity in mesenchymal tumors and critical CNS penetration, as the CNS is a frequent extra-thoracic failure site. Correlative studies will evaluate molecular genetics (DICER1 and p53 status) and a noninvasive circulating tumor DNA (ctDNA) biomarker assay for treatment monitoring and relapse detection. Radiotherapy-related rationales include the need for first-ever consistent and evaluable local control approaches to address thoracic recurrence in advanced types.
Materials/Methods: ARAR2331 is a Phase 3 study evaluating standardized therapy for all PPB types. Major eligibility criteria include patients <= 21 years of age with newly diagnosed PPB. For Types II and III, a novel "window" design assesses the objective response rate (CR+PR) to two initial cycles of vincristine, topotecan, and cyclophosphamide (VTC). Patients subsequently receive standard ifosfamide, vincristine, dactinomycin, and doxorubicin (IVADo) followed by consolidation based on window therapy response. For Type I, the trial uses prospectively defined criteria to refine indications for adjuvant vincristine, dactinomycin, and cyclophosphamide (VAC/VA) chemotherapy to reduce exposure in lower-risk patients.
Radiotherapy-related protocol objectives include:- Standardization of Local Control: Assessing the delivery of definitive or adjuvant primary site, regional nodal, and hemithorax radiotherapy (RT) for Types II and III PPB during the consolidation phase to improve local control.
- Metastatic Consolidation: Evaluating the role of metastatic site-directed consolidative RT (including SRS, SBRT, and WBRT) for bone, brain, and distant nodal sites.
- Advanced Modality Assessment: Investigating the safety and feasibility of utilizing highly conformal techniques, including proton therapy, IMRT/VMAT, and intraoperative radiotherapy (IORT), in very young children.
- Patterns of Failure: Quantifying the impact of standardized RT guidelines on patterns of recurrence and survival.
Results: Enrollment is ongoing; the study was activated on March 17, 2025, and no data analysis is available.
Conclusion: As the inaugural prospective trial for Pleuropulmonary Blastoma, ARAR2331 possesses the potential to establish the definitive standard of care for this rare malignancy.