Testing a Standardized Approach to Surgery and Chemotherapy for Type I Pleuropulmonary Blastoma or the Addition of an Anti-cancer Drug, Topotecan, to the Usual Treatment for Types II and III Pleuropulmonary Blastoma

Phase 3

Not yet recruiting

• Conditions: Pleuropulmonary Blastoma
• Interventions: Procedure: Biospecimen Collection; Other: Patient Observation; Procedure: Computed Tomography; Procedure: Bone Scan; Drug: Cyclophosphamide; Biological: Dactinomycin; Procedure: Resection; Procedure: Ultrasound Imaging; Drug: Dexrazoxane; Drug: Vincristine; Drug: Doxorubicin; Procedure: Echocardiography; Drug: Ifosfamide; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Procedure: Positron Emission Tomography; Drug: Topotecan

• Registration Number: NCT06647953
• Lead Sponsor: Children's Oncology Group

Brief Summary

This phase III trial tests how well surgery plus chemotherapy compared to surgery alone works in treating patients with type I pleuropulmonary blastoma (PPB), and tests how well surgery plus standard chemotherapy with the addition of topotecan works compared to surgery plus standard chemotherapy alone in treating patients with type II and III PPB.
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Detailed Description

PRIMARY OBJECTIVE:

I. To determine the overall response rate (complete response \[CR\] + partial response \[PR\]) to 2 cycles of window therapy with vincristine, topotecan and cyclophosphamide in children with Types II and III pleuropulmonary blastoma (PPB) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

SECONDARY OBJECTIVES:
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Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2024-10-10
• Study First Submitted QC: 2024-10-16
• Study First Posted: 2024-10-18
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-03
• Last Update Posted: 2024-12-05
• Study Start: 2025-03-17
• Primary Completion: 2029-03-31
• Study Completion: 2029-03-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 110

Inclusion Criteria

• 21 years of age or younger

• Newly diagnosed PPB. Note that patients with known germline DICER1 variant or mosaicism with a large, solid unresectable thoracic mass with imaging features characteristic for Type II or III PPB are eligible without histologic confirmation of the diagnosis if a biopsy of the mass is not considered safe or feasible

  • Individuals are eligible based on institutional diagnosis of Type I, Ir, II or III PPB diagnosed within 60 days prior to enrollment. Children with Type II or III PPB at risk for clinical decompensation may receive protocol therapy while awaiting rapid central pathology review. Children with Type I or Ir PPB will be assigned to chemotherapy vs. observation based on imaging and central pathology review diagnosis. Type I and Ir patients should not begin chemotherapy prior to return of central pathology results

• For patients with Type II or III PPB (within 7 days prior to enrollment): A serum creatinine based on age/gender as follows:

  • Age: 1 month to < 6 months - Maximum Serum Creatinine (mg/dL): 0.4 (Male), 0.4 (Female)
  • Age: 6 months to < 1 year - Maximum Serum Creatinine (mg/dL): 0.5 (Male), 0.5 (Female)
  • Age: 1 to < 2 years - Maximum Serum Creatinine (mg/dL): 0.6 (Male), 0.6 (Female)
  • Age: 2 to < 6 years - Maximum Serum Creatinine (mg/dL): 0.8 (Male), 0.8 (Female)
  • Age: 6 to < 10 years - Maximum Serum Creatinine (mg/dL): 1 (Male), 1 (Female)
  • Age: 10 to < 13 years - Maximum Serum Creatinine (mg/dL): 1.2 (Male), 1.2 (Female)
  • Age: 13 to < 16 years - Maximum Serum Creatinine (mg/dL): 1.5 (Male), 1.4 (Female)
  • Age: ≥ 16 years - Maximum Serum Creatinine (mg/dL): 1.7 (Male), 1.4 (Female) OR - A 24 hour urine creatinine clearance ≥ 60 mL/min/1.73 m^2 OR - A glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
  • Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility

• For patients with Type II or III PPB (within 7 days prior to enrollment): Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

• For patients with Type II or III PPB (within 7 days prior to enrollment): Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L

  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

• Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by radionuclide angiogram (within 21 days prior to start of protocol therapy)

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible as long as they are NOT receiving anti-retroviral agents that are strong inhibitors or inducers of CYP3A4

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Exclusion Criteria

• Administration of prior PPB-directed chemotherapy is an exclusion criterion. Prior treatment for another malignancy is not an exclusion criterion
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group I, Arm 1 (VAC1200/VA regimen)	Biospecimen Collection	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 1 (VAC1200/VA regimen)	Computed Tomography	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 1 (VAC1200/VA regimen)	Cyclophosphamide	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 1 (VAC1200/VA regimen)	Dactinomycin	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 1 (VAC1200/VA regimen)	Resection	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 1 (VAC1200/VA regimen)	Ultrasound Imaging	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 1 (VAC1200/VA regimen)	Vincristine	Patients undergo surgery on study. Patients receive vincristine IV on days 1, 8, and 15 of cycles 1-3 and 5-7, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and ultrasound throughout the study.
Group I, Arm 2 (observation)	Patient Observation	Patients undergo surgery on study. Patients undergo observation on study.
Group I, Arm 2 (observation)	Resection	Patients undergo surgery on study. Patients undergo observation on study.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Biospecimen Collection	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Bone Scan	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Computed Tomography	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Cyclophosphamide	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Dactinomycin	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Dexrazoxane	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Doxorubicin	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Echocardiography	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Ifosfamide	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Magnetic Resonance Imaging	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Multigated Acquisition Scan	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Positron Emission Tomography	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Resection	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Topotecan	See Detailed Description for Group II, Arm 3.
Group II, Arm 3 (VTC400, IVADo, VTC250, VAC1200 regimens)	Vincristine	See Detailed Description for Group II, Arm 3.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Biospecimen Collection	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Bone Scan	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Computed Tomography	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Cyclophosphamide	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Dactinomycin	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Dexrazoxane	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Doxorubicin	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Echocardiography	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Ifosfamide	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Magnetic Resonance Imaging	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Multigated Acquisition Scan	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Positron Emission Tomography	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Resection	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Topotecan	See Detailed Description for Group II, Arm 4.
Group II, Arm 4 (VTC400, IVADo, IVA regimens)	Vincristine	See Detailed Description for Group II, Arm 4.

Primary Outcome Measures

Name	Time	Method
Objective response	Up to 2 cycles (cycles = 21 days) of window therapy with vincristine, topotecan and cyclophosphamide	Response rates at the end of Cycle 2 will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method.

Secondary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	From date of enrollment to the earliest occurrence of relapse, disease progression, or death due to any cause, assessed up to 3 years	3-year PFS, along with the confidence intervals will be estimated using the Kaplan-Meier method. These results will be presented for Type II and III patients combined regardless of the timing of surgery.
Overall survival (OS)	From date of enrollment to date of death due to any reason, assessed up to 3 years	3-year OS, along with the confidence intervals will be estimated using the Kaplan-Meier method. These results will be presented for Type II and III patients combined regardless of the timing of surgery.