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.

Historically, most children with type I PPB had surgery and approximately 40% of children with type I PPB received chemotherapy following their surgery, usually for 22-42 weeks. There has not been a consistent standard for which children with type I PPB receive chemotherapy after surgery. For patients whose tumor has been removed completely with surgery, observation without chemotherapy may work as well as giving chemotherapy after surgery in preventing a return of the PPB tumor.

The standard chemotherapy for patients with types II or III PPB in the United States is four cycles of IVADo (ifosfamide, vincristine, dactinomycin, and doxorubicin) followed by 8 cycles of IVA (ifosfamide, vincristine and dactinomycin). Ifosfamide is in a class of medications called alkylating agents. It works by slowing or stopping the growth of tumor cells in the body. Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy (antineoplastic antibiotic). It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. Topotecan is in a class of medications called topoisomerase I inhibitors. It works by interfering with tumor cell DNA which kills them. Giving topotecan in addition to standard IVADo and IVA chemotherapy regimens may shrink the cancer as well as or better than the standard therapy or could decrease the chance the tumor spreads while causing fewer side effects.

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:

I. To estimate 3-year progression-free survival (PFS) and overall survival (OS) in children with Types II and III PPB.

II. To estimate 3-year PFS and OS in children with Type I PPB treated with surgery or surgery and chemotherapy using standardized guidelines.

EXPLORATORY OBJECTIVES:

I. To assess primary resection rate in children with Types I, II and III PPB using central radiology review and standardized surgical guidelines.

II. To assess surgical complications among those undergoing primary resection versus (vs.) biopsy followed by neoadjuvant chemotherapy for Types II and III PPB.

III. To establish a new cohort of prospectively treated children with newly diagnosed PPB which will serve as a comparison group for future novel agent trials.

IV. To evaluate toxicities in children treated for PPB including late cardiopulmonary toxicity.

V. To evaluate the molecular genetics/epigenetics of PPB and correlate with outcomes.

VI. To collect tumor tissue and serial blood samples for tumor profiling, liquid biopsies, and future correlative biology studies.

OUTLINE: Patients are assigned to 1 of 2 groups. For both groups, tumor tissue is centrally reviewed by a study pathologist. Blood samples are collected at specific clinical timepoints.

GROUP I (TYPE I/Ir PPB): Patients < 5 years old with Type I PPB whose tumor was not able to be completely removed by surgery are assigned to Arm 1. All other patients are assigned to Arm 2.

ARM 1 (VAC1200/VA REGIMEN): Patients receive vincristine intravenously (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, computed tomography (CT) and ultrasound throughout the study.

ARM 2: Patients undergo observation on study. This includes blood sample collection, chest CT, and ultrasound throughout the study.

GROUP II: (TYPE II/III PPB):

CYCLES 1-2 (VTC400 REGIMEN): Patients receive vincristine IV on days 1, 8, and 15 of each cycle, topotecan IV over 30 minutes on days 1-5 of each cycle, and cyclophosphamide IV over 15-30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-gated acquisition (MUGA) or echocardiography (ECHO), positron emission tomography (PET) or bone scan, CT, magnetic resonance imaging (MRI), and blood sample collection throughout the study.

Patients with complete response, partial response, or stable disease after cycle 2 are assigned to Arm 3. Patients with disease progression after cycle 2 are assigned to Arm 4. Patients also undergo surgery and radiation therapy as clinically indicated.

ARM 3:

CYCLES 3-6 (IVADo REGIMEN): Patients receive vincristine IV on day 1 of each cycle, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, ifosfamide IV over 3 hours on days 1-2 of each cycle, dexrazoxane IV over 5-15 minutes on days 1-2 of each cycle, and doxorubicin IV over 3-15 minutes on days 1-2 of each cycle. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES 7, 9, 11 (VTC250 REGIMEN): Patients receive vincristine IV on days 1, 8, and 15 of each cycle, topotecan IV over 30 minutes on days 1-5 of each cycle, and cyclophosphamide IV over 15-30 minutes on days 1-5 of each cycle. Treatment continues for 21 days every odd cycle for 3 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES 8, 10, 12 (VAC1200 REGIMEN): Patients receive vincristine IV on day 1 of each cycle, 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 each cycle. Treatment continues for 21 days every even cycle for 3 cycles in the absence of disease progression or unacceptable toxicity.

ARM 4:

CYCLES 3-6 (IVADo REGIMEN): Patients receive vincristine IV on day 1 of each cycle, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, ifosfamide IV over 3 hours on days 1-2 of each cycle, dexrazoxane IV over 5-15 minutes on days 1-2 of each cycle, and doxorubicin IV over 3-15 minutes on days 1-2 of each cycle. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES 7-12 (IVA REGIMEN): Patients receive vincristine IV on day 1 of each cycle, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and ifosfamide IV over 3 hours on day 1 of each cycle. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 24 months, then every 6 months until 5 years.

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/sex 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

Exclusion Criteria:

• Administration of prior PPB-directed chemotherapy is an exclusion criterion. Prior treatment for another malignancy is not an exclusion criterion
• Patients with known Charcot-Marie-Tooth disease
• 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