Title
A Phase 3 Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Pediatric and Adult Patients with Germ Cell Tumors

Description
Patients with standard risk 1 are randomized into 1 of 2 arms.

ARM I (CEb): Patients receive bleomycin intravenously (IV) over 10 minutes and carboplatin IV over 1 hour on day 1. Patients also receive etoposide IV over 1-2 hours on days 1-5. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study.

ARM II (PEb): Patients receive bleomycin IV over 10 minutes on day 1. Patients also receive etoposide IV over 1-2 hours and cisplatin IV over 1-3 hours on days 1-5. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study.

Patients with standard risk 2 are randomized into 1 of 2 arms.

ARM III (BEC): Patients receive bleomycin IV over 10 minutes on days 1, 8, and 15, etoposide IV over 1-2 hours on days 1-5, and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study.

ARM IV (BEP): Patients receive bleomycin IV over 10 minutes on days 1, 8, and 15, etoposide IV over 1-2 hours on days 1-5, and cisplatin IV over 1-3 hours on days 1-5. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study.

After completion of study treatment, patients are followed up every 2 months for 12 months, every 3-6 months to 24 months, every 6 months for years 3-5, and then annually for up to 10 years.

Objective
I. To evaluate whether a strategy of complete surgical resection followed by surveillance can maintain an overall survival rate of at least 95.7% at two years for pediatric, adolescent and adult patients with stage I (low risk) malignant germ cell tumors (Stratum 2), and at least 88% for patients with all stage/grade ovarian pure immature teratoma (Stratum 1).

II. To compare the event-free survival of a carboplatin versus (vs.) cisplatin-based regimen in the treatment of pediatric, adolescent and young adult patients with standard risk non-seminomatous germ cell tumors.

IIa. To compare the event free survival (EFS) of a carboplatin-based regimen (carboplatin [C] etoposide [E] bleomycin [b]) vs. a cisplatin-based regimen (cisplatin [P]Eb) in children (less than 11 years in age) with standard risk germ cell tumors (GCT).

IIb. To compare the EFS of a carboplatin-based regimen (BEC) vs. a cisplatin-based regimen (BEP) in adolescents and young adults (ages 11 - < 25 years) with standard risk GCT.

Treatment Patients with low-risk stage I grade 2, 3 ovarian immature teratoma or stage I non-seminoma malignant germ cell tumors (MGCT)s undergo observation and can transfer to standard risk arm at time of recurrence if eligibility criteria are met. Patients with stage I seminoma testicular MGCT undergo observation, and those with residual/recurrent disease are treated at the discretion of their physician. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or chest x-ray as well as blood sample collection throughout the trial to monitor for response and recurrence. Patients may also undergo a tumor biopsy throughout the trial.

Key Eligibility
Low Risk Stratum (Stage I Ovarian Immature Teratoma and Stage I Malignant GCT (all sites) Patients must be < 50 years of age at enrollment

Standard Risk 1: Patient must be < 11 years of age at enrollment

Standard Risk 2: Patients must be ≥ 11 and < 25 years of age at enrollment

Newly diagnosed patients must have histologic verification of a primary extracranial germ cell tumor

Elevation of serum tumor markers without histologic confirmation is not sufficient for entry on the trial

Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years
of age

Must have adequate Renal, Liver and Pulmonary Function

Has received prior cisplatin- or carboplatin-based chemotherapy regimen for malignancy including diagnoses other than germ cell tumor

Has experienced prior or ongoing hearing impairment due to chemotherapy or radiotherapy

Exclusion Criteria:

Stage 1 testicular cancer patients who have undergone primary RPLND (retroperitoneal lymph node dissection)

Pure dysgerminoma and pure seminoma

Pure mature teratoma, COG stage I with AFP > or equal to 1000 mg/mL

Pure immature teratoma COG Stage II - IV or FIGO Stage IC to IV

Poor risk disease (age ≥ 11 years old and COG Stage IV ovarian, COG

Stage III or IV EG, or IGCCC intermediate or poor risk testicular), or Primary CNS germ cell tumor

Can not be pregnant or breast feeding

No prior systemic therapy

Applicable Disease Sites
Anal; Bladder; Breast; Cervix; Colon and Rectum; Endocrine cancers; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Ill-Defined Sites; Kidney; Liver; Lung; Lymphoma; Melanoma/Skin cancer; Ovary; Pancreas; Prostate; Sarcoma; Stomach; Thyroid; Unknown Sites; Uterus

Participating Institutions
Gundersen Health System; UW Health University Hospital